Metal-Mediated Vinylogous Nazarov Cyclization Reaction

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Electronic Theses and Dissertations Theses, Dissertations, and Major Papers

9-13-2019

Somaiah Khalid Almubayedh University of Windsor

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This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. METAL-MEDIATED VINYLOGOUS NAZAROV CYCLIZATION REACTION

Somaiah Khalid Almubayedh

A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Windsor

Windsor, Ontario, Canada

Metal-Mediated Vinylogous Nazarov Cyclization Reaction

Somaiah Khalid Almubayedh

APPROVED BY:

______R. Dembinski, External Examiner Oakland University

______I. Al-Aasm School of the Environment

______J. Rawson Department of Chemistry and Biochemistry

______S. Johnson Department of Chemistry and Biochemistry

______J. Green, Advisor Department of Chemistry and Biochemistry

September 13, 2019

DECLARATION OF ORIGINALITY

I hereby certify that I am the sole author of this thesis and that no part of this dissertation has been published or submitted for publication.

I declare that, to the best of my knowledge, my dissertation does not infringe upon anyone’s copyright nor violate any proprietary rights and that any ideas, procedures, or any other material from the work other people included in my dissertation, published or otherwise, are fully acknowledged in accordance with the standard referencing practices.

Furthermore, to the extent that I have included copyright material that surpasses the bounds of fair dealing within the meaning of the Canada Copyright Act, I certify that I have obtained written permission from the copyright owner(s) to include such material(s) in my dissertation.

I declare that this is a true copy of my dissertation, including any final revisions, as approved by my dissertation committee and the Graduate Studies office, and that this dissertation has not been submitted for a higher degree to any other University or

Institution.

iii ABSTRACT

The Nazarov cyclization reaction has been used as an effective method to synthesize cyclopentanones. While 6-membered ring systems can be available by way of the homo Nazarov variant, 7-membered ring formation involving a Nazarov-type reaction is very rare, and completely unknown thermally. Using the established concept of the ability of the alkyne-Co2(CO)6 moiety to enable the formation of g-carbonyl cations and the good stability of this generated cation, 7-membered ring formation via the vinylogous

Nazarov reaction with electron deficient enones has been investigated.

The desired aryl substituted enyone-Co2(CO)6 complex precursors for the cyclization reaction have been prepared from commercially available starting materials, using a series of reactions that include Sonogashira cross-coupling, desilylation, organolithium reactions with aldehydes, oxidation and complexation reactions. The treatment of the respective complex precursors, using SnCl4 as a suitable Lewis acid, successfully generated cycloheptynone-Co2(CO)6 complexes. The substitution effects have been examined, showing that introducing a bulky group at the a-position to the carbonyl enhances the cyclization efficiency by enabling the desired s-trans/s-trans conformation.

On the other hand, b-substituting with an R group other than H atom reduces the reaction rate and allows formation of the desired 7-membered ring only in very low yield.

Preparation of appropriate dienynone-Co2(CO)6 complex substrates allowed expansion of the reaction scope to non-aromatic starting materials. Successful reductive decomplexation of the cycloheptynone-Co2(CO)6 unit also was demonstrated.

iv DEDICATION

I dedicate this research to my sweet daughter Ritaj and my son Rakan, my beloved husband Mohammed, and to my parents Sondos and Khalid who gave me all their love and care.

No words can express my gratitude for them, for they have always supported and encouraged me.

ACKNOWLEDGMENTS

First and foremost, I would like to express my sincere gratitude to my advisor Prof. James Green for the continuous support of my Ph.D. study and related research, for this patience, motivation, and immense knowledge. His support and guidance helped me in all the time of research and writing of this thesis.

Beside my advisor, I would like to thank the rest of my thesis committee: Prof. Jeremy Rawson and Prof. Sam Johnson, for their insightful comments and encouragement, and for reading my thesis, but also for the hard question which motivated me to widen my research from various perspectives, and Dr. Ihsan Al-Aasm for his willingnes to act as the outside examiner. I would also like to thank past and present members of the Green group: Dr. Mariam Mehdi, Page Penner, Nathan Bazinski, Scott Adams and Brent St Onge and

Jeff Battersby for all their advice, assistance, support, and friendship.

I would like to extend further thanks to Matt Revington for his assistance with the NMR spectroscopy, to Joe Lichaa for all his technical support, and to Chemistry and Biochemistry department members in the surrounding labs and department for their friendship, interactions, and for sharing their chemicals. The big thanks to the

v administrative staff: Marlene Bezaire and Elizabeth Kickham for their assistance during my four years at the University of Windsor; to the CCC previous and current staff: Jerry and Alina. I thank to Audithya Nyayachavadi for his assistance with the UV spectroscopy.

I would like to give special thanks for Mohammad Tarawneh of the Chemistry department at the University of Jordan in Amman, who provided me an opportunity to tap his expertise in Chemistry for sharing the knowledge, and for valuable comments during my Ph.D. work. Finally, I must express my very profound gratitude to my parents and to my spouse for providing me with unfailing support and continuous encouragement throughout my years and years of study, and to my siblings. This accomplishment would not have been possible without them. Thank you.

vi TABLE OF CONTENTS

DECLARATION AND ORIGINALITY ...... iii

ABSTRACT ...... iv

DEDICATION ...... v

ACKNOWLEDGMENT ...... v

LIST OF FIGURES ...... xii

LIST OF SCHEMES ...... xiii

LIST OF TABLES ...... xix

LIST OF ABBREVIATIONS ...... xx

CHAPTER 1 INTRODUCTION ...... 1

1.1 THE NICHOLAS REACTION ...... 1

1.1.1 STEREOCHEMISTRY OF THE NICHOLAS REACTION ...... 7

1.2 NICHOLAS REACTIONS: SCOPE OF NUCLEOPHILES ...... 12

1.2.1 NICHOLAS REACTION WITH HYDRIDE NUCLEOPHILES ...... 12

1.2.2 NICHOLAS REACTION WITH ARENE AND HETEROARENE

NUCLEOPHILES ...... 13

1.2.3 NICHOLAS REACTION WITH ALLYLSILANE AND

ALLYLSTANNANE NUCLEOPHILES ...... 16

1.2.4 NICHOLAS REACTION WITH ENOLIC NUCLEOPHILES ...... 18

vii 1.2.5 NICHOLAS REACTION WITH SILYL ENOL ETHER NUCLEOPHILE

…………………………………………………………...... 19

1.2.6 THE REACTION OF ELECTROPHILES WITH COBALT-

COORDINATED ENYNES ...... 20

1.3 ANGLE STRAINED CYCLOALKYNES ...... 24

1.3.1 STABILIZATION OF CYCLOALKYNES WITH TRANSITION METALS

OTHER THAN COBALT ...... 26

1.3.2 STABILIZATION OF CYCLOALKYNES WITH COBALT ...... 27

1.4 THE SYNTHESIS OF CYCLOHEPTYNEDICOBALT COMPLEXES ...... 28

1.5 DECOMPLEXATION OF CYCLOALKYNE-Co2(CO)6 ...... 32

1.6 PERICYCLIC REACTIONS ...... 37

1.7 THE NAZAROV CYCLIZATION REACTION ...... 39

1.7.1 STEREOSELECTIVITY IN THE NAZAROV REACTION ...... 40

1.7.2 REGIOSELECTIVITY IN THE NAZAROV REACTION ...... 42

1.7.3 STERIC INFLUENCE OF a-SUBSTITUENTS IN THE NAZAROV

REACTION ...... 43

1.7.4 THE POLARIZED NAZAROV REACTION ...... 44

1.7.5 THE NAZAROV REACTION OF ALLENYL VINYL KETONES ...... 45

1.7.6 NAZAROV REACTION OF AROMATIC SUBSTRATES ...... 47

1.7.7 THE INTERRUPTED NAZAROV REACTION ...... 49

1.7.8 ISO-NAZAROV ...... 51

viii 1.7.9 HOMO-NAZAROV REACTION ...... 55

1.7.10 CROSS-CONJUGATED TRIENES-VINYLOGOUS NAZAROV

REACTIONS ...... 60

1.7.11 THE NAZAROV REACTION OF UNSATURATED a-DIKETONES ..... 62

1.8 SYNTHETIC APPLICATIONS OF THE NAZAROV CYCLIZATION ...... 63

1.8.1 USE OF THE “CLASSICAL” NAZAROV REACTION IN SYNTHESIS

……………………………………………………………………………63

1.8.2 USE OF THE “POLARIZED” NAZAROV REACTION IN

SYNTHESIS…...... 64

1.9 NEW DIRECTIONS OF THE NAZAROV CYCLIZATION REACTION ...... 65

1.10 RESEARCH OBJECTIVE ...... 68

CHAPTER 2 RESULTS AND DISCUSSION: METAL-MEDIATED VINYLOGOUS

NAZAROV REACTIONS ...... 69

2.1 RETROSYNTHETIC ANALYSIS ...... 69

2.2 VINYLOGOUS NAZAROV CYCLIZATION REACTION ...... 71

2.2.1 CARBOCYCLIC ARENE CASE ...... 71

2.2.1.1 CARBOCYCLIC ARENE SYSTEM REACTIVITY ...... 83

2.2.2 VINYLOGOUS NAZAROV CYCLIZATION REACTION: a-

SUBSTITUTED CASES ...... 84

2.2.3 VINYLOGOUS NAZAROV CYCLIZATION REACTION: b-

SUBSTITUTED CASE ...... 93

ix 2.2.4 VINYLOGOUS NAZAROV CYCLIZATION REACTION: INDOLE

SYSTEM...... 98

2.2.5 VINYLOGOUS NAZAROV CYCLIZATION REACTION: NON-

AROMATIC SYSTEM ...... 101

2.3 PROPOSED CYCLIZATION REACTION MECHANISM ...... 106

2.4 REDUCTIVE DECOMPLEXATION OF CYCLOHEPTYNONE-Co2(CO)6

COMPLEXES ...... 109

CHAPTER 3 CONCLUSIONS AND FUTURE WORK ...... 112

3.1 CONCLUSION ...... 112

3.2 FUTURE WORK ...... 113

CHAPTER 4 EXPERIMENTAL SECTION ...... 119

4.1 GENERAL METHODS AND MATERIALS ...... 119

4.2 INSTRUMENTATION ...... 120

4.3 EXPERIMENTAL DATA ...... 121

REFERENCES ...... 165

APPENDIX ...... 178

STARTING MATERIAL (A) ...... 180

TRANSITION STATE (A) ...... 180

PROTONATED PRODUCT (A¢) ...... 182

STARTING MATERIAL (B) ...... 184

x TRANSITION STATE (B) ...... 186

PROTONATED PRODUCT (B¢) ...... 188

STARTING MATERIAL (C) ...... 190

TRANSITION STATE (C) ...... 192

PROTONATED PRODUCT (C¢) ...... 194

STARTING MATERIAL (D) ...... 196

TRANSITION STATE (D) ...... 198

PROTONATED PRODUCT (D¢) ...... 200

E-2.6h ...... 202

Z-2.6h ...... 204

VITA AUCTORIS ...... 206

DISSERTATION-RELATED CONFERENCE PRESENTATIONS ...... 207

xi LIST OF FIGURES

Figure 1.1: Thermodynamic stability (pKR+) and electrophilic reactivity (E) of propargylium-metal complexes...... 7

Figure 1.2: Structural and electronic features of propargyl-dicobalt complexes ...... 8

Figure 1.3: Mayr scale of electrophilicity and nucleophilicity...... 22

Figure 1.4: Cycloalkyne categories based on their occurrence...... 26

Figure 1.5: Cycloheptyne in the presence of cobalt moiety...... 28

Figure 1.6: Nazarov reactivity increase with a-substitution...... 43

Figure 1.7: The steric rationale behind increased reactivity of allenyl ketones...... 46

Figure 1.8: Two strategies for formal homo-Nazarov reaction...... 58

Figure 2.1: Proposed reactivity trend of the carbocyclic arenes system...... 84

Figure 2.2: Apparent trend of the reactivity of different a-substitutions toward the cyclization...... 92

Figure 2.3: Optimized geometries of (E-2.6h) and (Z-2.6h) isomers ...... 95

3 Figure 2.4: Calculated coupling constant J for the cycloheptyne-Co2(CO)6 with b- methyl substitution...... 97

Figure 2.5: UV-vis spectra of anisole system ...... 100

Figure 2.6: A series of non-aromatic precursors...... 102

Figure 2.7: Alkene isomerization during cyclization reaction...... 105

Figure 2.8: Reported N and E values according to Mayr’s scale...... 108

Figure 2.9: NOESY correlations observed in 2.28...... 110

Figure 3.1: Electron-withdrawing group a-site to carbonyl...... 114

Figure 3.2: HOMO orbitals of a heptatrienyl cation...... 116

xii LIST OF SCHEMES

Scheme 1.1: Nicholas reaction of dicobalt hexacarbonyl-stabilized propargylic cation. .. 2

Scheme 1.2: Proposed reaction mechanism of Nicholas reaction...... 3

Scheme 1.3: A variety of nucleophiles reacting with propargyl-hexacarbonyl dicobalt cation...... 5

Scheme 1.4: Diastereoselective reactions of enol silanes with a- substituents and propargyldicobalt cations...... 9

Scheme 1.5: Diastereoselectivity with stereogenic centers in the nucleophile-chiral auxiliaries...... 10

Scheme 1.6: Stereogenic centers in in the alkynedicobalt unit...... 10

Scheme 1.7: Racemization via antarafacial migration and its transition state (TS)...... 11

Scheme 1.8: Deoxygenated alkyne-complexes formation using triethylsilane as nucelophile...... 12

Scheme 1.9: Nicholas reaction with indole nucleophile generating various products. .... 14

Scheme 1.10: Ag(I) catalytic Nicholas reaction with indole nucleophile...... 15

Scheme 1.11: Nicholas reaction of sulfonium propargylic cation with anisole nucleophile...... 15

Scheme 1.12: Nicholas reaction of alcohol-derived propargylic cation with anisole...... 16

Scheme 1.13: Nicholas reaction with allylsilane nucleophile...... 17

Scheme 1.14: Diastereospecific Nicholas reaction using allyltributylstannane nucleophile...... 18

Scheme 1.15: Nicholas reaction with enolic nucleophiles...... 18

xiii Scheme 1.16: Intermolecular MBH reaction using dicobalt hexacarbonyl complexed acetylenic acetals...... 19

Scheme 1.17: Asymmetric Nicholas reaction with silyl enol ether nucleophile...... 20

Scheme 1.18: Nicholas reaction of a,b-functionalized alkyne complexes...... 21

Scheme 1.19: Nicholas reaction of unsaturated enyne dicobalt hexacarbonyl-stabilized propargylic cation...... 24

Scheme 1.20: Cyclohexyne-platinum (n = 1) (1.35a) and cycloheptyne-platinum (n = 2)

(1.36b) complexes...... 27

Scheme 1.21: The synthesis of the first cycloheptyne-Co2(CO)6 complex (1.38)...... 29

Scheme 1.22: Synthesis of cycloheptyne-Co2(CO)6 complexes via intramolecular

Nicholas reactions...... 29

Scheme 1.23: Intramolecular synthesis of cycloheptyne-Co2(CO)6 with arenes nucleophiles...... 30

Scheme 1.24: Synthesis of cycloheptyne-Co2(CO)6 via ring closing metathesis by Green.

...... 31

Scheme 1.25: Other examples of the formation of cycloheptyne-dicobalt complexes. ... 32

Scheme 1.26: CAN oxidative reduction...... 33

Scheme 1.27: Iodine oxidative decomplexation...... 33

Scheme 1.28: Reductive decomplexation via Birch conditions...... 34

Scheme 1.29: Tributyltin hydride decomplexation...... 35

Scheme 1.30: Hydrosilation of dicobalthexacarbonyl moiety via triethylsilane...... 36

Scheme 1.31: Hydrosilylation/fluorodesilylation of alkynedicobalt hexacarbonyl complex...... 36

xiv Scheme 1.32: Sodium hypophosphite decomplexation...... 37

Scheme 1.33: Cyclic transition state example of a pericyclic reaction...... 38

Scheme 1.34: The five sub-divisions of pericyclic reactions...... 39

Scheme 1.35: Mechanism of the classical Nazarov reaction...... 40

Scheme 1.36: Diastereospecificity in the Nazarov cyclization for both (a) thermal and (b) photochemical processes...... 41

Scheme 1.37: Enantioselective Nazarov cyclization promoted by a chiral Lewis acid. .. 41

Scheme 1.38: Nazarov reactions giving non-regioselective elimination...... 42

Scheme 1.39: Silicon-directed Nazarov reactions giving regioselective elimination...... 42

Scheme 1.40: Fluorine-directed Nazarov reactions to give regioselective elimination. .. 43

Scheme 1.41: Rationale behind the design of the polarized Nazarov reaction...... 44

Scheme 1.42: The polarized Nazarov reaction with only one “polar” a-substituent...... 45

Scheme 1.43: The Nazarov cyclization of allenyl vinyl ketones...... 46

Scheme 1.44: Nazarov reaction of aryl vinyl ketone...... 47

Scheme 1.45: Nazarov reaction of aryl vinyl ketone to produce an indanone...... 48

Scheme 1.46: Nazarov reaction to produce oxazolidinone-substituted aryl vinyl ketones.

...... 49

Scheme 1.47: The interrupted Nazarov reaction...... 50

Scheme 1.48: An intramolecular interrupted Nazarov reaction...... 50

Scheme 1.49: Iso-Nazarov reaction...... 51

Scheme 1.50: 2H-pyran intermediate trapping...... 52

Scheme 1.51: First example of iso-Nazarov to afford a 2-cyclopentenone...... 53

Scheme 1.52: Silicon directed iso-Nazarov reaction...... 53

xv Scheme 1.53: Domino or cascade iso-Nazarov reaction...... 54

Scheme 1.54: Classical Nazarov reaction (a) versus homo-Nazarov (b)...... 55

Scheme 1.55: Formal homo-Nazarov reaction for the cyclization of vinyl-cyclopropyl ketones...... 56

Scheme 1.56: Mechanism of formal homo –Nazarov reaction...... 57

Scheme 1.57: Formal homo-Nazarov reaction for non-electron-rich aryl substituents. .. 59

Scheme 1.58: Formal enantioselective homo-Nazarov reaction for electron-rich aryl substituents...... 59

Scheme 1.59: β-Heteroatom substituent mediated formal homo-Nazarov cyclization. ... 60

Scheme 1.60: Cyclization of cross-conjugated trienes via vinylogous Nazarov cyclization...... 61

Scheme 1.61: Proposed mechanism for the vinylogous Nazarov reaction...... 62

Scheme 1.62: Frontier MO study of vinylogous Nazarov cyclization...... 63

Scheme 1.63: Synthetic route to racemic trchodiene...... 64

Scheme 1.64: Total synthesis of racemic roseophilin...... 65

Scheme 1.65: One-pot photochemical isomerization-condensation-photocyclization cascade...... 66

Scheme 1.66: Proposed reaction mechanism for 6p light-induced Nazarov reaction. .... 67

Scheme 1.67: Proposed mode of cyclization by vinylogous Nazarov cyclization...... 68

Scheme 2.1: DFT results for the vinylogous Nazarov cyclization reactions of phenyl- and

3-methoxyphenyl cationic intermediates at the B88-PW91/dzvp level...... 70

Scheme 2.2: Proposed retrosynthetic method to the formation of the vinylogous Nazarov reaction precursors...... 71

xvi Scheme 2.3: Synthesis of a,b-unsaturated ketone toward the vinylogous Nazarov reaction precursor...... 72

Scheme 2.4: The series of transformations to obtain cross-conjugated ketones for the di- and trimethoxy arenes...... 75

Scheme 2.5: Preliminary vinylogous Nazarov cyclization attempt using BF3•OEt2...... 79

Scheme 2.6: The obtained para- 2.7a and ortho- 2.7a¢ products using SnCl4 via the vinylogous Nazarov cyclization...... 81

Scheme 2.7: Experimental support for regiochemical selectivity using electron rich benzenes in Nicholas reactions...... 81

Scheme 2.8: The formation of two possible regioisomers...... 82

Scheme 2.9: Synthetic route toward the formation of the complexed cross-conjugated dienynone for b-substituted case...... 94

Scheme 2.10: Vinylogous Nazarov cyclization of b-methyl via SnCl4 as a Lewis acid…

...... 96

Scheme 2.11: Synthesis of the vinylogous Nazaro cyclization precursor of indole system.

...... 99

Scheme 2.12: Cyclization result of indole-based system...... 100

Scheme 2.13: DFT results for the vinylogous Nazarov cyclization reactions of enyne group cationic intermediates at the B88-PW91/dzvp level...... 101

Scheme 2.14: Non-aromatic precursors formation toward the vinylogous Nazarov cyclization...... 103

Scheme 2.15: Proposed reaction mechanism of the vinylogous Nazarov cyclization reaction...... 107

xvii Scheme 2.16: Reductive decomplexation via hydrosilation conditions...... 109

Scheme 2.17: Protodesilylation using trifluroacetic acid...... 111

Scheme 3.1: One-pot Nicholas-Nazarov reactions...... 115

Scheme 3.2: Orbital symmetry of the heptatrienyl cation intermediate...... 117

Scheme 3.3: Designed precursors of the iso-Nazarov approach to form a seven- membered ring...... 118

Scheme 3.4: Pauson-Khand reaction of the synthesized cycloheptyne-Co2(CO)6...... 118

xviii LIST OF TABLES

Table 2.1: Oxidation reaction of alcohol 2.4a using different reaction conditions...... 74

Table 2.2: Oxidation reaction conditions and results for di- and trimethoxy arenes. .... 76

Table 2.3: Complexation reaction via dicobalt octacarbonyl (Co2(CO)8)...... 77

Table 2.4: Vinylogous Nazarov cyclization results using di- and tri- methoxyarene moieties...... 83

Table 2.5: Formation of alcohols of various a-substituted substrates...... 86

Table 2.6: Formation of cross-conjugated ketones of various a-substituted substrates. . 87

Table 2.7: The complexation results of various a-substitutions substrates enynones. .... 89

Table 2.8: Cyclization reaction results of various a-substituted via SnCl4 as a Lewis acid.

...... 90

Table 2.9: Formation of two isomers via cyclization reaction of the non-aromatic system.

...... 104

Table 2.10: N values of various enyne groups...... 108

xix LIST OF ABBREVIATIONS

d Chemical shift nmax Wavelength

NMR Nuclear Magnetic Resonance aq. Aqueous

BF3•OEt2 Boron trifluoride etherate

Bn Benzyl brsm Based on recovered starting material

BTMSA Bis(trimethylsilyl)acetylene

CAN Ceric ammonium nitrate

Cu(OTf)2 Copper(II)triflate

Cy Cyclohexyl d Doublet

DCE Dichloroethane

DCM Dichloromethane dd Doublet of doublets ddd Doublet of doublets of doublets

DMF Dimethylformamide

DTBP Di-tert-butyl peroxide

E Electrophilicity parameter

E+ Electrophile

EAS Electrophilic aromatic substitution

xx EDG Electron donating group ee Enantiomeric Excess equiv Equivalent

Et Ethyl

Eu(OTf)3 Europium(III)trifluoroethanesulfonate

EWG Electron withdrawing group

FT-IR Fourier-Transform Infrared Spectroscopy

HBF4•OEt2 Tetrafluroboric acid diethyl ether complex

HOMO Highly Occupied Molecular Orbital

HRMS High Resolution Mass Spectrometry

EI Electron Ionization iPr Isopropyl

IR Infrared Spectroscopy

J Coupling constant

L.A. Lewis acid

LUMO Lower Unoccupied Molecular Orbital

Me Methyl m/e Mass/Charge ratio m Multiplet m.p. Melting point

MBH Morita-Baylis-Hillman

MS Mass Spectroscopy

N Nucleophilicity parameter

xxi N2 Nitrogen

NaH2PO2•H2O Sodium hypophosphite nBuLi n-Butyllithium

NMO N-Methylmorphine N-oxide

NOESY Nuclear Overhauser Effect Spectroscopy

Nu- Nucleophile p-TSA p-Toluenesulfonic acid

PCC Pyridinium chlorochromate

PDC Pyridinium dichromate

Ph Phenyl ppm Parts per million q Quartet

RCM Ring closing metathesis

RT Room temperature s Singlet

Sat. Saturated

SN Nucleophile-specific sensitivity parameter

SOMO Singly Occupied Molecular Orbital t Triplet

TBAF Tetrabutylammonium fluoride

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TIPS Triisopropylsilyl

xxii TLC Thin layer chromatography

TMP Trimethyoxyphenyl

TMS Trimethylsilyl

TMSA Trimethylsilylacetylene

TMSOTf Trimethylsilyl trifluromethanesulfonate

TPAP Tetrapropylammonium perruthenate

TsOH p-Toluenesulfonic acid

UV Ultraviolet

xxiii CHAPTER 1 INTRODUCTION

1.1 THE NICHOLAS REACTION

An important approach to altering the reactivity of organic compounds is the complexation of the compound’s p-system to a transition metal fragment. This may enhance, suppress, or invert the reactivity normally associated with the organic system.

Among these the use of alkyne-dicobalt hexacarbonyl Co2(CO)6 complexes has gained increasing prominence in organic synthesis,1-3 with highly efficient developments performing advanced transformations. In organic chemistry, acetylene-Co2(CO)6 complexes are used mainly for three major reactions:4 (i) the Pauson-Khand reaction to form cyclopentenones,5-10 (ii) the use of the cobalt moiety as a useful protecting group11 for acetylenic compounds because of its ease of addition and removal, and (iii) the Nicholas reaction,1-3, 12-19 where nucleophilic additions to cobalt-complexed propargylic cations occur.

The chemistry of the Nicholas reaction, or chemistry of hexacarbonyl(µ-h2- propargylium)cobalt cations, was first reported in 1972.20 The Nicholas reaction allows efficient substitution reactions of the dicobalt hexacarbonyl complexes of propargyl ethers, alcohols, and acetates, resulting in the formation of new carbon-heteroatom and/or carbon- carbon covalent bonds (Scheme 1.1).21 The Nicholas reaction also has been exploited for the synthesis of bioactive compounds.3

1 1. Co2(CO)8 R3 R3 R2 2. Lewis acid, Nu R2 OR Nu 3. Oxidative demetalation R1 R1

Scheme 1.1: Nicholas reaction of dicobalt hexacarbonyl-stabilized propargylic cation.

20 Nicholas and Petit investigated the use of the Co2(CO)6 moiety as a protecting group for the alkyne carbon-carbon triple bond, and within that work were drawn to the facile nature of the mild, acid-mediated dehydration of dicobalt hexacarbonyl-complexed propargyl alcohols to their corresponding 1,3-enyne derivatives. Propargylic alcohols without a Co2(CO)6 moiety did not react under the same reaction conditions. Dehydration of cobalt-free propargyl alcohols required harsh conditions, such as strongly acidic conditions and those with considerably high temperature (80-200 oC).

The Nicholas reaction per se is comprised of the two central reactions in a four reaction process. The step prior to the substitution reaction involves an addition of dicobalt octacarbonyl to a propargylic alcohol, ether, or acetate derivative (1.1), which leads to the

2 formation of a dicobalt complex, µ-h -Co2(CO)6-alkyne (1.2), as shown in Scheme 1.2.

The centerpiece of this process is the formation of a stable (propargylium)Co2(CO)6 cation

(1.3-I and 1.3-II) from the hexacarbonyldicobalt complex (1.2) with the help of a protic or

Lewis acid, by the departure of an appropriate leaving group. The reactivity of the triple bond is suppressed by the dicobalt complex, while the propargylic position becomes quite reactive.20 Immediate addition of a nucleophile furnishes the desired substitution product

19 1.4. The mechanism of Nicholas reaction can be best described as an SN1 process. The cobalt complex can be either reductively or oxidatively removed in a separate reaction

2 following the nucleophilic incorporation, to give the substituted alkyne (1.5) (or alkene, in the case of reduction). Alternatively, the Nicholas reaction products can be further functionalized via cobalt-mediated reactions, such as the Pauson-Khand reaction.22-24 A wide variety of Brønsted or Lewis acids can be utilized in the reaction, with commonly used ones being tetrafluoroboric acid (HBF4•OEt2), and boron trifluoride (BF3•OEt2), whereas ceric ammonium nitrate [(NH4)2•Ce(NO3)6, CAN] is used most commonly for the demetallation reaction as a powerful oxidant.

OR OR R2 R R2 2 (OC) Co Co2(CO)8 (OC)3Co 3 R R3 R3 Lewis acid 3 R1 (OC) Co (OC)3Co 3 R R1 1

1.1 1.2 1.3-I

Nu Nu Oxidative R2 R2 R2 (OC)3Co Nu (OC)3Co demetalation R3 R3 R 3 (OC) Co (OC)3Co 3 R R1 R1 1

1.5 1.4 pKR+ = -5.50 - -7.40 1.3-II

+ (Ph3C = -6.60)

Scheme 1.2: Proposed reaction mechanism of Nicholas reaction.

The cationic complex (1.3) possesses a positive charge delocalized onto the alkynyl-cobalt carbonyl moiety21 and an unsymmetrical, but structurally fluxional h2/h3-

25 binding of the two Co(CO)3 groups to the propargyl unit, which is important with respect

3 to the regio- and stereoselectivity of their reactions with different nucleophiles (Scheme

1.3). The nucleophiles that react well include hydride donors to give 1.6,26-28 heteroatomic molecules such as amines and alcohols to give 1.7,29-32 and carbon-based nucleophiles; these include organometallic reagents to give 1.8,33-36 electron-rich aromatics to give

1.9,21,37-39 allyl metalloids to give 1.10, 40-42 and enols or enol derivatives to give 1.11.25a,43-

4 R3 R H-MRn (OC)6Co2 2 H (M = B, Al, Sn) R1 1.6

R3 HZRn (OC)6Co2 R2 ZRn (Z = O, N, P, S) R1

1.7

R3 LnM'-R4 (OC)6Co2 R2 (M = Al, Fe, B) R4 R3 R1 (OC)6Co2 1.8 R2 R1 1.3 R H-Ar-Z 3 (OC)6Co2 R2 Ar-Z

R1 1.9 (Z = H, OR, OH, NR2, Cl, etc)

R RnQ 3 (OC)6Co2 R2 (Q = B, Si, Sn) R1 1.10

OQRn R3 (OC) Co R R 6 2 2

(Q = B, Si, Sn) R 1 O R 1.11

Scheme 1.3: A variety of nucleophiles reacting with propargyl-hexacarbonyl dicobalt cation.

5 Interestingly, the propargyldicobalt hexacarbonyl cation has been easily observed by 1H NMR spectroscopy at low temperature in trifluoroacetic acid-d, and shows very small downfield shifts of the propargylic hydrogen atoms relative to the precursor alcohol complex.20 In the 13C NMR spectra, only mild deshielding of the propargyl carbon atom relative to the parent alcohol complex is observed.46 Furthermore, α-[(ethynyl)dicobalt hexacarbonyl] carbonium ions have been isolated by Connor and Nicholas47 as stable, dark red solids upon treatment with excess tetrafluoroboric acid etherate.

The intermediate propargylic cations have a thermodynamic stability similar to that

+ of the trityl carbocation, Ph3C , (Scheme 1.2), as reflected in the pKR’s for equilibration

+ with their corresponding alcohol complexes. The cations’ measured pKR values range from -6.80 to -7.4047 (or -5.50 as mentioned in another reference48), which is comparable

+ 49 with pKR value of the trityl cation, -6.60. Mayr observed that the measured electrophilicity values (E), which are log scale measures of reactivity (see Figure 1.3,

+ section 1.2.6), correlated well with the thermodynamic parameter (pKR ), and the position of such complexed cations is close to α-ferrocenyl and dibenzopyrilium ions (Figure 1.1).

A detailed study revealed only a marginal effect of substituent (close to a 101 difference) on the propargyl unit, whereas an extensive impact of the ligand on the metal center is evident. For example, propargyl-Co2(CO)6 (E ca. - 2) and propargyl-Co2(CO)5(PPh3) (E ca. - 7) differ by a factor of 105.

6 Ln M R1 MLn

R2 R3

pKR+ E

M2L2n = Co2(CO)6 (1.3') -7.0 -1

Co2(CO)5(PPh3) _ -7

Cp2Mo2(CO)4 +3.5 _

R , R and R = H 1 2 3

Figure 1.1: Thermodynamic stability (pKR+) and electrophilic reactivity (E) of propargylium-metal complexes.

Cation formation was also experimentally demonstrated through IR spectroscopy, showing an increased carbonyl C-O absorption frequency (2085, 2105 and 2130 cm-1), as compared to the precursor substrate (2025, 2050 and 2090 cm-1), which is evidence of the charge delocalization.1 The IR frequency shift indicates greater C-O bonding, due to the decreasing d(Co) à p*(CO) back-donation in the electron deficient cations.47 It has been concluded that the organometallic Co2(CO)6 unit has powerful electron donating abilities.

1.1.1 STEREOCHEMISTRY OF THE NICHOLAS REACTION

The stereochemical disposition of the Nicholas reaction depends on a variety of factors, including the thermodynamic stability, electrophilic reactivity, and structural and

+ electronic features of the (propargylium)M2Ln systems. The cations are fluxional, undergoing both enantiomerization (1.3a to 1.3a¢) and syn-/anti-interconversion, (Figure

7 1.2).3 The energy barriers are approximately 10 kcal/mol and 13 kcal/mol, respectively

(depending on the substitution and ligand), which are low enough to be overcome at low temperature; this can be the driving force for stereoselective reactions, some of which are discussed below.

H H R R2 antara facial migration R3 R 1 (faster) 1 R3 R2 3 (OC) Co(CO) 3Co (OC)3Co enantiomerization Co(CO)3 R 1.3a' R 1.3a 4 4 (enantiomerization) supra facial migration supra facial migration (slower) (slower)

syn/anti isomerization syn/anti isomerization (syn/anti isomer) R3 R2 H H R 1 R2 antara facial migration R3 R1 (faster) (OC) 3Co Co(CO) Co(CO)3 (OC)3Co 3 enantiomerization R 1.3b' 1.3b 4 R4

Figure 1.2: Structural and electronic features of propargyl-dicobalt complexes.50a

Highly syn- diastereoselective reactions of enol silanes with a- substituents

(preferentially with (Z)- enols) and propargyldicobalt cations have been observed (Scheme

1.4), explained mechanistically by the lowest energy transition state model 1.12. This model features an anti-periplanar orientation of enol and propargyl complex, which is favored over the higher energy model 1.12¢ (containing a syn-periplanar orientation).50b

8 Me O Me O (OC)6Co2 (OC)6Co2 Me Lewis acid, Ph Ph (OC) Co o 6 2 OTMS CH2Cl2, -78 C R Me R Me OMe Me Ph R anti syn

R = TMS, Ph, Me R R (OC) Co (OC)3Co 3 Lewis acid = BF OEt , EtAlCl 3 2 2 H H Co(CO) Me Co(CO)3 Me 3 Ph Ph Me Me TMSO H H OTMS 1.12 1.12'

Scheme 1.4: Diastereoselective reactions of enol silanes with a-substituents and propargyldicobalt cations.

Chiral auxiliaries also have found good use in stereoselective reactions with propargyldicobalt cations. Diastereoselectivities of ca. 97:3 with the unsubstituted propargyldicobalt cation were observed with the boron enolates of norephedrine derived oxazolidinone chiral auxiliaries, whereas 12:1 dr’s were observed in substrates containing alkylated propargyldicobalt cations (Scheme 1.5). These results were explained by the lowest steric repulsion being in transition state models 1.13 and 1.13¢.25a The model 1.13 is considered more favorable than 1.13¢, and because of this reaction with the boron enolate is expected to more rapidly generate tha syn-alkylation product.

9 Me (OC)6Co2 OMe TMS O O O Me Bu2BOTf, O Me CH Cl , -10 oC Co2(CO)6 Co2(CO)6 2 2 O N O N 80 % Me TMS Me TMS O Ph Ph OBBu2 O N 12:1 Me syn/anti Bu O Bu Ph Me B O Ph B O O Ph Me antrafacial Me O O N migration N Bu Bu enantiomerization Me Me H H Co(CO) TMS H 3 Me TMS Me H Co(CO) (OC) Co 3 3 (OC)3Co 1.13 1.13'

Scheme 1.5: Diastereoselectivity with stereogenic centers in the nucleophile-chiral auxiliaries.

In cases where the alkynedicobalt unit is attached to a stereogenic center, the reaction can be dominated by the complex, since the Co2(CO)6 unit is bulky, being between isopropyl and t-butyl in size. Thus, the group will normally adopt an equatorial orientation in cyclic systems, affording moderate to very high diastereomeric ratios in systems capable of epimerization (Scheme 1.6).51-53a

Co2(CO)6 Co2(CO)6 Co2(CO)6 TMS TMS TMS O CF3SO3H O O OAc (0.1 equiv) OAc OAc

OAc CH2Cl2, RT OAc OAc (90%), 19:1

Scheme 1.6: Stereogenic centers in the alkynedicobalt unit.

10 In contrast, the enantiomeric enrichment at a single chiral center undergoing a

Nicholas reaction is lost, due to the low barriers to antarafacial migration, except in the cases of very rapid reactions.53b As shown in Figure 1.2, an enantiomerization occurs at the propargylic center of the cation through rapid antarafacial migration which has a low energy barrier, leading a very rapid to racemization process. This is evident by the work by Schreiber et al. on the allylation of a selected substrate (Scheme 1.7). Even though enantiomerically pure substrates were made via reaction with (+)-isopinocampheol and separation of the diastereomers, individual treatment with a Lewis acid and allyl TMS led to racemic product 1.14. Clearly, the antarafacial migration of cationic carbon center is faster than the allylation process thus allylation occurs on both faces, giving both the enantiomers in equal proportion (Scheme 1.7).25a

Me Me Me Me

OH (OC) Co ROH 6 2 pTsOH Me Me Me O (OC) Co O CH Cl , 4A MS (OC)6Co2 H 6 2 Me Me 2 2 Me H Me Me

H Me

TMS (OC)6Co2 Me BF3 OEt2 (OC)3Co Co(CO)3 o Me CH2Cl2, -78 C racemic Me 1.14 TS (antarafacial migration)

Scheme 1.7: Racemization via antarafacial migration and its transition state (TS).

11 There are several other examples of diastereoselective or enantioselective Nicholas reaction that provide good to excellent stereoselectivities via 1,2-asymmetric induction54 or 1,4-asymmetric induction,55-57 including chiral acetal complexes,57 a system with camphoric acid derived backbone,59 cases with stereogenic centers at the leaving group60,61 or chirality in the nucleophile,62,63 and intramolecular propargylation reactions using hydride nucleophiles.64,65

1.2 NICHOLAS REACTIONS: SCOPE OF NUCLEOPHILES

1.2.1 NICHOLAS REACTION WITH HYDRIDE NUCLEOPHILES

The following scheme illustrates the reaction of the (propargylium)Co2(CO)6 complexes after the addition of hydride nucleophiles. While many reductants, such as borohydrides 26 and boranes,27 have been successful, silanes28 are the most commonly employed hydride sources for this reduction. Moderate to excellent yields are usually obtained. Scheme 1.8 illustrates the formation of the deoxygenated alkyne-complexes

(1.15) using triethylsilane and boron triflate etherate in 70 % yield.28

TBDPSO TBDPSO Et SiH, BF OEt HO 3 3 2 (OC)6Co2 (OC)6Co2 CH2Cl2

H H 1.15 70%

Scheme 1.8: Deoxygenated alkyne-complexes formation using triethylsilane as nucelophile.

12 1.2.2 NICHOLAS REACTION WITH ARENE AND HETEROARENE

NUCLEOPHILES

At room temperature, the isolated or generated (in situ) propargylium-cobalt complexes react with electron-rich aromatic nucleophiles, such as benzenoids (with NR2 or OR substituents) and heteroaromatic systems, including furans, thiophenes, pyrroles, and indoles, to produce the desired propargylated complex with arenes/heteroarenes. The typical regioselectivity preferences for electrophilic aromatic substitution are followed

(i.e., para- > ortho- >> meta-) for the benzenoid cases, and reaction occurs at C2 for heteroaromatics and C3 for indole cases. Despite the fact that polysubstitution of the arene is possible and sometimes observed, careful experimentation can minimize this issue.

Indole is a heteroaryl nucleophile which can be used to generate polycyclic compounds having diverse applicability. Propargylations of indole using dicobalthexacarbonyl stabilized propargyl cations was described by Roth et al.39 It’s a tandem reaction that may involve electrophilic and nucleophilic addition. The reaction between the indole compound and the propargylic cation under the varying conditions led to the formation of specifically 3-substituted products (Scheme 1.9). If C3 is unsubstituted

(R5 = H), then there is a possibility of double addition of dicobalthexacarbonyl stabilized propargyl cations gives product 1.18 from 1.17 if R3 = H. As shown in Scheme 1.9, when

C3 substituted (R5 ≠ H), then the N-substituent also greatly affects the fate of product. If

R3 ≠ H, then product 1.16 may transformed into 1.19 by an added nucleophile; 1.20 is formed if R3 = H.

13 R OR 1 (OC)6Co2 (Co)6Co2 Co2(Co)6 R2 Co2(Co)6 R2 R 1 R2 R1 R 2 R1 R 4 BF3 OEt2 N R4 N H 1.17 1.18 OR R = H (OC)6Co2 5 R3 = H R2 Co2(Co)6 R1 R2 R1 BF3 OEt2 R5 R5 3 R5 = H R4 R = H N R 3 1.19 4 R N 2 3 Co2(Co)6 R3 H R2 R1

R4 Co2(Co)6 N R2 R1 R3 R = H R5 1.16 3 R4 N 1.20

Scheme 1.9: Nicholas reaction with indole nucleophile generating various products.

The following scheme shows the use of indole via a Au(I) and Ag(I)-catalyzed

Nicholas reaction. The mixture of Ph3PAuCl (5 mol%)/NaBArF (7.5 mol%) or Ag(I) catalyst itself in (5%) produces a good to excellent yield of compound 1.21, derived from the attack of the C-3 indole carbon atom (Scheme 1.10).66

14 H Co2(CO)6

Co (CO) H 2 6 OH AgSbF6 (5 mol %), 2 h (100 %) OR

N Ph3PAuCl (5 mo l%) H NaBArF (7.5 mol %), 1 h (81 %) N H

1.21

Scheme 1.10: Ag(I) catalytic Nicholas reaction with indole nucleophile.

El-Amouri et al. have studied the different complexes of the propargylic cation with sulfides, phosphines, and pyridine for their reactivity.67 They observed that stability in propargyl cation was increased due to the presence of heteroatoms like S, P and N, due to the actual formation of sulfonium, phosphonium, and ammonium salts. Sulfonium derived propargylic cations were found to be selective toward reaction with anisole as nucleophile

(Scheme 1.11).

OMe

BF4 OMe (OC)6Co2 (OC) Co (OC)6Co2 6 2 R S 2 CH2Cl2 R1 R R1 R3 OMe 1 1.22 1.23a 1.23b R1 = H R2, R3 = Me, Et, iPr

Scheme 1.11: Nicholas reaction of sulfonium propargylic cation with anisole nucleophile.

The sulfide complex 1.22 were studied in cases with varying S-alkyl groups and

Me and Et substituted case were found to be less reactive as compared to iPr substituted

15 one. A reaction of the sulfide complex having Et groups slowly reacted with anisole affording two regioisomers 1.23a and 1.23b with the ratio of 2:1, favoring para- product; this is comparatively better than previously reported the analogous reaction by Lockwood and Nicholas21 with harsher reaction condition. They used strong acids as a catalyst to promote the reaction with complexed alcohols having alkyl substituents which favors para-

products with the bulkiness of substituents as described below (Scheme 1.12). HBF4Me2O is showed better yield in middle of line and selectivity toward the para- product than

TFA/TFAA, whereas disustituted complexes favor exclusively para- product due to propargyl-site bulkiness.

OMe R OH 2 R3 R2 R3 OMe (OC) Co (OC)6Co2 (OC)6Co2 6 2 R2 R3 acid, 0 oC R1 R R1 OMe 1

R1 = H acid % yield para- : ortho- R2, R3 = H TFA 46 : 31 R2, R3 = H HBF4 Me2O 49 : 35 R2 = Me, R3 = H HBF4 Me2O 53 : 25 R2, R3 = Me HBF4 Me2O 78 : -

Scheme 1.12: Nicholas reaction of alcohol-derived propargylic cation with anisole.

1.2.3 NICHOLAS REACTION WITH ALLYLSILANE AND

ALLYLSTANNANE NUCLEOPHILES

Allylsilane and -stannane nucleophiles successfully participate in reactions with the propargylium-cobalt complexes produced from a number of different precursors (Scheme

16 1.13). Like other allylsilane-electrophile combinations, the allylsilane reacts selectivity at the g- site. O'Boyle and Nicholas were first to report the allylation of propargyl dicobalt hexacarbonyl cation via allylsilanes, which served an easy route for the synthesis of 1,5- enynes (1.24).40 The reaction involves mixing allylsilanes, with cationic cobalt salts in

DCM at 0 ºC, which gives allylated products in good yields ranging from 70-97%.

Decomplexation of cobalt complex was carried out using Fe(NO3)3•9H2O in ethanol to afford 1.24 (Scheme 1.13). This reaction was successful in the generation of quaternary centers despite the competing elimination reaction.

R R R 1) 4 5 R 5 R2 BF4 2 R4 (OC) Co 6 2 TMS R6 R6 R3 R3 o CH2Cl2, 0 C R1 R1 2) Fe(NO3) 9H2O 1.24 ethanol, 0 o C R1 = H R2, R3 = H, Me, Ph R4 = H R4 , R5 = H, Me,

Scheme 1.13: Nicholas reaction with allylsilane nucleophile.

An additional example in this class involves the dicobalt hexacarbonyl complexed acetylenic aldehyde (1.25) which was treated with allyltributylstannane using BF3•OEt2

Lewis acid, generating compound 1.26 in a good yield. Stereospecificity is also good with

E-allyl derivatives favouring anti-products, while Z-allyl derivatives favour syn-3,4- products (Scheme 1.14).68 Although some question exists of classification, such reactions are usually classified as Nicholas reactions if they are Lewis acid mediated.

17 SnBu3 O OH OH (1 equiv) H Ph BF3 OEt2 (1 equiv), Ph Ph Co2(CO)6 o CH2Cl2, -20 C Co2(CO)6 1.26 Co2(CO)6 1.25 (95%) syn:anti = 75:25

Scheme 1.14: Diastereospecific Nicholas reaction using allyltributylstannane nucleophile.

1.2.4 NICHOLAS REACTION WITH ENOLIC NUCLEOPHILES

Enol derivatives of carbonyls, and related compounds, are effective in Nicholas reactions to give α-propargyl carbonyl compounds.44 While enol silanes and silyl ketene acetals are the most popular versions of this class of nucleophiles, enamines and carbonyls with a high enol content (i.e. b-diketones) also participate well. In some cases ordinary enolizable ketones will work, if they are the reaction solvent (Scheme 1.15).

O O (OC)6Co2 O OH 1. HBF Me O, CH Cl H 4 2 2 2 H Co (CO) o 2 6 -78 C O 2. diketone, -78 oC to 0 oC, 1 h 95%

Scheme 1.15: Nicholas reaction with enolic nucleophiles.

A noteworthy manifestation of this reactivity includes the dicobalt hexacarbonyl complexed acetylenic acetals (1.27), which undergo intermolecular Morita-Baylis-Hillman

18 (MBH) and Nicholas reactions with enone (1.28) as the nucleophile source. These generate products 1.29 in good yields (Scheme 1.16).69

1) a) tetrahydrothiophene (1.2 equiv), R1 BF3 OEt2 (2.5 equiv) O OEt O o (OC)6Co2 CH2Cl2, 0 C OEt OEt R1 b) NEt3 (3 equiv) R o R CH2Cl2, 0 C 1.27 1.28 2) decomplexation 1.29

Scheme 1.16: Intermolecular MBH reaction using dicobalt hexacarbonyl complexed acetylenic acetals.

The cationic propargylic dicobalt complexes also react with various nucleophiles in an intramolecular fashion. Specific examples will be introduced in cycloalkyne section.

1.2.5 NICHOLAS REACTION WITH SILYL ENOL ETHER

NUCLEOPHILE

Ljungdahl et al.70 reported the asymmetric Nicholas reaction using chiral phosphoramidite ligands. The propargylic alcohol was complexed with cobalt carbonyl and a chiral phosphoramidite ligand, which later was reacted with the silyl enol ether. Among the screened ligands, S-BINOL-pyrrolidine derived ligand (L1) gave good results with 35% yield, 74% ee for silyl enol ether nucleophile (Nu) leading to product 1.30 (Scheme 1.17).

19 OH OH

1) Co2(CO)8 , CH2Cl2, RT Co2(CO)4(L)2 O O 2) L (2 equiv), toluene, 50 oC Ph

o 1) BF3 OEt2, Nu, CH2Cl2, -30 C to RT

o 2) CAN, THF:H2O (9:1), -10 C O 1.30

O O R1 L = P N P N O O R2

L1 S-BINOL

OSiMe3 Nu =

Scheme 1.17: Asymmetric Nicholas reaction with silyl enol ether nucleophile.

1.2.6 THE REACTION OF ELECTROPHILES WITH COBALT-

COORDINATED ENYNES

Recently, the role of cobalt-complexed propargyl cations in organic synthesis, with its vast range of possible nucleophilic partners, has been expanded to include the synthesis of α, β-functionalized alkyne complexes involving cation 1.3 as a critical intermediate

(Scheme 1.18). These tactics include starting materials like enynes (1.31), and complexes of epoxy-alkynes (1.33), which allow the regioselective β-addition of electrophiles.

20 To produce 1.32 from 1.31, an enyne complex, the latter undergoes the β-addition of an electrophile (like H+ or RCO+) in a regioselective manner, followed by α-attack by nucleophiles (Nu-). Similarly, epoxide complexes (1.33) also undergo a regioselective β- addition of an electrophile (often H+) and then α-attack of a nucleophile (Nu-) to give β- hydroxy-α-functionalized derivatives (1.34).

(OC) Co (OC) Co 6 2 R Nu 6 2 R2 E+/Nu- 2 R R 3 R R3 1 1 E 1.31 1.32

(OC) Co R2 (OC)6Co2 R Nu 6 2 H+/Nu- 2 O OH R1 R1 R3 R3 1.33 1.34

Scheme 1.18: Nicholas reaction of a,b-functionalized alkyne complexes.

Mayr et al. built up a helpful quantitative electrophile-nucleophile reactivity scale known to be “Mayr Scales”.71 It reflects the reactivity of electrophiles (E+) and nucleophiles (Nu-) and suggests that a reaction of an E+ / Nu- pair can be possible at room temperature if the value of (E + N) > –5. It is also helpful in predicting the ratio of products for competing nucleophiles for a reaction (Figure 1.3).

The reaction rate constant can be calculated as:

log k20°C = SN(N + E)

21 Where: E = electrophilicity parameter; N = nucleophilicity parameter; SN = nucleophile-specific sensitivity parameter (N and SN are solvent-dependent).

most electrophilic + 6 Ph3CH

For reaction at room temperature: 4 (N+E) > -5 N E

BCl -7 2 H 3

O Ph

Cr(CO)3 -5 0 electrophile of interest

Co2(CO)6 (OC)6Co2 Ph Me Si -3 -2 3 Co2(CO)6 MeO

Co (CO) 2 6 anisole propargyl electrophile -1 -4 SiMe3

enynes Co2(CO)5(PPh3)

Ph SiMe3 Co (CO) 1 -6 2 6 CO2R

CO2R SiMe3 MeO O SiMe (OC)3Fe 3 carbocyclic arene 3 -8 OMe (Ph3P)(OC)5Co2 Ph OMe

MeO OMe O Ph 5 -10 Pd(P(OPh)3)2 OSiMe3

-12 N 7 H Ph

Pd(PPh3)2 most nucleophilic

Figure 1.3: Mayr scale of electrophilicity and nucleophilicity.

22 Alkynes and enynes are considered to be nucleophiles. Enyne dicobalt complexes, i.e. precursors to hexacarbonyl propargyl cation complexes, fall into this category, and were found to have N values of -1 to +1 on the Mayr scale. While considered less reactive nucleophiles, these enyne complexes would be expected to react with the electrophiles of

E > -4, as in Figure 1.3. Furthermore, these measurements of enyne-Co2(CO)6 complexes demonstrate > 106 more rapid reactions as compared to the free alkyne.71,72

As a result of the above considerations, it is a known tactic to react a conjugated enyne with dicobalt hexacarbonyl to make the enyne complex, which undergoes regioselective addition of an electrophile E+, and to have the resultant propargyldicobalt cation to react with nucleophile to afford a functionalized alkynedicobalt complex (Scheme

1.19).72

23 Y TMS H (OC) Co H Co2(CO)6 6 2 + E+ Co2(CO)8

o TMS TMS CH2Cl2, -78 C X

Y Y TMS

- TMS (Nu ) Co2(CO)6 E+ =

- Ti2Cl9 X X

Scheme 1.19: Nicholas reaction of unsaturated enyne dicobalt hexacarbonyl-stabilized propargylic cation.

In conclusion, the Nicholas reaction offers significant synthetic advantages due to the stability of the cobalt complexed propargylic cation, the protected nature of the alkyne and the regio- and stereoselective reaction possibilities with many nucleophiles. As will be seen, the formation of medium-sized cycloalkyne complexes also becomes possible with this chemistry.

1.3 ANGLE STRAINED CYCLOALKYNES

The consideration of angle strained cyclic compounds, as well as their generation, has been a critical theme in many areas of chemistry due to fundamental interest in structure, and due to the existence of cyclic natural products for which such alkynes might serve as intermediates.73 Medium-sized cycloalkynes (7 to 12-membered ring sizes) are synthetically challenging and sometimes most difficult to obtain. It is well known that the

24 geometry of the triple bond is linear (180o), and thus cycloalkynes have an inherent reason for limited stability.74,75 The eight-membered system, cyclooctyne, that was first synthesized in 1953 by Blomquist,76 is the smallest ring size that can accommodate this deformed geometry and still be isolable as a stable species. Unlike the isolable medium- sized cycloalkynes, the smaller homologues, i.e., cyclopentyne, cyclohexyne, and cycloheptyne, containing five-, six-, and seven-membered rings, respectively, are non- isolable. They are able to exist as transient and highly reactive reaction intermediates that oligomerize very rapidly.77-79 These cycloalkynes must be generated in rapid reactions in the absence of any reactive chemicals that could be trap to the triple bond.80 The characterization of these highly reactive intermediates is also difficult due to their limited lifetimes. The half-life time of cyclopentyne is around one second at a low temperature -

78 oC.81 In dilute dichloromethane at room temperature the half-life of the seven-membered ring cycloheptyne is less than one minute; however, it can be increased to one hour at -78 oC.82 Under analogous conditions, the lifetime of cyclohexyne is a few seconds at -110 oC.

At present, there is no experimental result proving the existence of smaller ring sized cyclic alkynes, such as four or three-membered ring cases (Figure 1.4).80,83

25 lower ring-strain

isolable

transient intermediates

non-existent

higher ring-strain

Figure 1.4: Cycloalkyne categories based on their occurrence.

1.3.1 STABILIZATION OF CYCLOALKYNES WITH TRANSITION

METALS OTHER THAN COBALT

Transition metal complexes have, in many instances, played critical roles in organic chemistry. The Nicholas reaction (vide infra) is just one example of their ability to stabilize highly reactive species; in addition they may activate organic substrate to highly selective attack in both inter- and intra-molecular reactions. Upon complexation of transition metal fragments to dienes, alkenes, or alkynes, new reactivities are often available, and traditional ones are often suppressed. Central to the work in this dissertation is the complexation of transition metal moieties to alkynes, which may be obtained from simple precursors and give alternative strategies to other methods in medium-sized ring synthesis. The cycloalkynes that have short life time such as small- and medium-sized and transient molecules can be greatly stabilized by coordination to various transition metals. Bennett and Yoshida84 published structure of stable bis(triphenylphosphine)platinum complexes of

26 cyclohexyne and cycloheptyne, containing six- and seven-membered rings, respectively.

These complexes were generated by the reduction reaction of the appropriate 1,2- dibromocycloalkene (1.35); using 1% sodium amalgam in the presence of Pt(PPh3)3. The cyclohexyne complex, Pt(C6H8)(PPh3)2 (1.36a), and the cycloheptyne complex,

Pt(C7H10)(PPh3)2 (1.36b), were isolated in good yields (Scheme 1.20). In 1989, Bennett reported increased reactivity of the cycloalkyne-Pt(PPh3)2 complexes with reduction of their ring size was reduced, such as the cyclopentyne complex, Pt(C5H6)(PPh3)2, was a very reactive solid.73 The group also reported the first example of dinickel(0) complex of 1,4- benzdiyne.

1% Na/Hg, Pt(PPh3)3 Br THF, RT,4 h Pt(PPh3)2 Br n = 0, 59 % n = 0,1 n = 1, 81 % n = 0,1 1.35 1.36a n=0 1.36b n=1

Scheme 1.20: Cyclohexyne-platinum (n = 1) (1.35a) and cycloheptyne-platinum (n = 2) (1.36b) complexes.

1.3.2 STABILIZATION OF CYCLOALKYNES WITH COBALT

The dicobalt hexacarbonyl protecting group, Co2(CO)6, has been commonly used to enable the cyclization reaction of the geometrically disfavoured fragments by enhancing the stability of the bent alkyne moiety.85 In 1959, Sly86 reported on the change to the linear geometry of alkyne after the complexation with M2L2 fragment. Upon the complexation of

27 the triple bond of diphenylacetylene with a Co2(CO)6 fragment, the alkyne bond angle is reduced from 180o to 137o-138o. In conjunction with the previously discussed significant stabilization of cations formed at the propargylic site of alkyne-Co2(CO)6 complexes, the alkyne-bending feature has allowed chemists to obtain cycloalkynedicobalt complexes that couldn't be obtained for the metal-free counterparts (Figure 1.5). For example, alkyne-

Co2(CO)6 complexes of cycloheptyne (or larger) complexes are quite easily formed, and their cyclohexyne analogues are possible in several cases.87,88

(OC)3Co Co(CO)3 Co2(CO)6

Cycloheptyne-Co2(CO)6 -long term thermal stability

Figure 1.5: Cycloheptyne in the presence of cobalt moiety.

1.4 THE SYNTHESIS OF CYCLOHEPTYNEDICOBALT

COMPLEXES

Schreiber and co-workers, in as early as 1986,50 reported the use of the Nicholas reaction in the formation of the first cycloheptyne-dicobalt complex (1.38) with an exocyclic vinyl unit, using a Lewis acid-mediated intramolecular cyclization reaction of the propargylic ether complex linked to an allysilane (1.37; Scheme 1.21). Following the exact methodology Schreiber also successfully synthesized six- and eight-membered ring systems.

28 TMS

BF OEt OMe 3 2 CH2Cl2

55 % Co2(CO)6 Co2(CO)6 1.37 1.38

Scheme 1.21: The synthesis of the first cycloheptyne-Co2(CO)6 complex (1.38).

The Green group89 also developed the preparation of this class of compounds using

Nicholas chemistry. The first efforts were driven by the development of the g-carbonyl cation-Co2(CO)6 fragments and their ability to be used as suitable precursors for the formation of cycloheptynedicobalt complexes. With further experimentations using a variety of substrates, a series of allylsilane- containing propargylic acetates were found to be suitable precursors. Intramolecular Nicholas reactions in the presence of BF3•OEt2 formed the cycloheptynes (1.39) with an endocyclic alkene unit, in good yields (Scheme

1.22).

SiR3 BF3 OEt2 R1 OAc CH2Cl2

R o 1 0 C Co2(CO)6 Co (CO) 2 6 1.39

R = Me, R1 = H R1 = H, (89 %) R = Et, R1 = H R1 = H, (87 %) R = Et, R1 = Ph R1 = Ph, (84 %) R = Me, (85 %) R = Et, R1 = Me 1

Scheme 1.22: Synthesis of cycloheptyne-Co2(CO)6 complexes via intramolecular Nicholas reactions.

29 Scheme 1.23 shows the reaction of propargyl acetate and ether complexes with electron-rich arenes, producing seven- membered ring systems. Eight- membered systems are also formed similarly. For the seven-membered ring systems, complexes of both, benzocycloheptynes, and dibenzocycloheptynes may be formed.90,91 The use of arenes without the presence of an electron-donating group cyclize successfully; however, higher yields are obtained with more highly electron-rich arenes and with π-excessive heterocycles. For the eight-membered ring, dibenzocyclooctyne complexes and their dibenzocyclooctynone analogues are readily available.92

R1 R1

Co2(co)6 BF3 OEt2 (3 equiv) Co (co) i-Pr NEt (1.5 equiv) 2 6 OAc 2 R2 o R 0 C to RT, CH2Cl2, t 2

R3 R5 R3 R5 R4 R4

R1 R2 R3 R4 R5 t(h) Yield OMe OMe OMe OMe H 6 (71%) OMe H Me H Me 6 (85%) OMe H OMe OMe OMe 4.5 (91%)

CO2Me OMe OMe OMe H 5 (84%)

Scheme 1.23: Intramolecular synthesis of cycloheptyne-Co2(CO)6 with arenes nucleophiles.

The propargyl cation intermediacy, or the Nicholas reaction, is most often used in the synthesis of these cycloalkyne complexes; however, it is not the sole method to access cycloheptyne-dicobalt complexes. An additional method of quick access to cycloheptyne-

30 Co2(CO)6 complexes is the use of ring closing metathesis (RCM) chemistry. The first RCM reaction on alkyne-cobalt complexes was reported by Green in 2001,93 where the cycloheptyne-Co2(CO)6 complexes were obtained via the RCM of the corresponding acyclic dienes (1.40), using Grubbs’ (I) catalyst (Cy3P)2Cl2Ru=CHPh, , in 43 to 95% yields

(Scheme 1.24).

R X (Cy3P)2Cl2Ru=CHPh (cat.)

X Co2(CO)6 Co (CO) 2 6 R R = H. OAc, n-Pr 1.40 43-95% X = H. OAc, n-Pr

Scheme 1.24: Synthesis of cycloheptyne-Co2(CO)6 via ring closing metathesis by Green.

There are many other methods used on rare occasions for the access to the formation of these complexes. These include 5+2 cycloaddition reactions,94 Diels-Alder reactions,95 and Michael reactions (Scheme 1.25).96

31 a) Cycloaddition reaction

TIPSO O OTIPS OTIPS EtAlCl (OC)6Co2 2 Co2(CO)6 BzO H 83%

b) Diels-Alder reaction O O O

silica gel H2, Pd/C O Co (CO) O O 2 6 EtOAc, 0 oC

Co2(CO)6 Co2(CO)6 62% c) Michael reaction

O O O (OC) Co 6 2 Co2(CO)6 Co (CO) MeAlCl2 (2 equiv) Ph Ph 2 6

TBSO DTBP (0.1 equiv) o OTBS O Ph CH2Cl2, -40 C, 44 h 30% 43%

Scheme 1.25: Other examples of the formation of cycloheptyne-dicobalt complexes.

1.5 DECOMPLEXATION OF CYCLOALKYNE-Co2(CO)6

As mentioned above, the protection of alkynes is often done by preparing the alkyne-Co2(CO)6 complexes, and the latter are also used as a mediator for the formation of carbon-carbon bonds, as acetylene dicobalt hexacarbonyl complexes are stable.97 Most generally, the Nicholas reaction utilizes propargyl alcohol derivatives complexed with octacarbonyl dicobalt for treatment of various nucleophiles. The Nicholas reaction products are still complexes, from which removal of Co2(CO)6 is done normally by oxidation. In most cases oxidative decomplexation yields an alkyne with triple bond in its original location.

32 The most widely used reagents of oxidative decomplexation include Fe(NO3)3 in alcohol (ROH), ROH/THF, or CH2Cl2, ceric ammonium nitrate (CAN) in acetone, MeOH,

MeOH/H2O, MeOH/Et2O, or MeCN, iodine in benzene or THF, triethylamine N-oxide in

THF, MeOH, or CHCl3; and N-methylmorpholine N-oxide (in conjunction with 1,4-

i t 98 cyclohexadiene) in THF, CH2Cl2, PrOH, DMF, or CCl4/ BuOH. Though CAN (Scheme

1.26a) and molecular iodine99 (Scheme 1.27) are the most popular oxidizing agents for the removal of Co2(CO)6, the use of CAN can result in the unusual formation of an anhydride product with angle strained alkynes (Scheme 1.26b).100 Another efficient method includes use of 2-aminoethanol at room temperature.101

Co (CO) 2 6 (NH4)2Ce(NO3)6 (CAN) TBDPSO O TBDPSO H TMS o O H acetone, 0 C, 75 % H TMS H

TIPOS TIPOS (NH4)2Ce(NO3)6 (CAN) O

o Co2(CO)6 acetone, 0 C, 83 % O

unusal anhydride O

Scheme 1.26: CAN oxidative decomplexation.

Co (CO) 2 6 excess I2, THF

CO2Me 10 h, 97 % CO2Me OMe OMe

Scheme 1.27: Iodine oxidative decomplexation.

33 The situation is somewhat different in medium-sized cycloalkyne dicobalt complexes, as the cobalt is required for stability. Oxidative decomplexation for this case will destroy the cycloalkyne ring, thus it is not an applicable tactic for this type of molecule.

When reductive decomplexation is carried out, alkenes are generated instead of alkynes and it is applicable for both cyclic and acyclic alkyne-hexacarbonyldicobalt systems. The most common reductive decomplexation methods include: H2 over Rh/charcoal in EtOH, lithium in liquid NH3, H2 over Wilkinson’s catalyst in benzene, tributyltin hydride

(Bu3SnH) in benzene, sodium hypophosphite (NaH2PO2•H2O) in 2-methoxyethanol, and triethylsilane (Et3SiH) in benzene or 1,2-dichloroethane or triphenylsilane (Ph3SiH) in benzene. The latter pair of methods actually form the respective vinylsilanes.

High-pressure hydrogenation with Rh catalysts (Wilkinson’s catalyst),102,103 or

Birch reduction conditions using lithium metal were the initially chosen methods to afford the desired alkenes; an example is shown in Scheme 1.28.104 These methods largely have been replaced by one of three techniques (vide supra) for reductive removal of the cobalt carbonyl unit.

Co2(CO)6 O O o H Li, NH3, -78 C H

15 min, 75 % MeO MeO

Scheme 1.28: Reductive decomplexation via Birch conditions.

34 Tributyltin hydride (Scheme 1.29) works efficiently for endo and exocyclic alkyne dicobalt hexacarbonyl systems and it does not interfere with a free hydroxyl group (-OH).

105 The major disadvantage of this method is that undesired isomerization of olefin was sometimes obtained. Furthermore, over-reduction is observed in some cases by reducing cycloalkynone complexes to the cycloalkanone.92,94 A recent modification has been reported that employs the use of N-methylmorpholine N-oxide (NMO; 10 equivalents) along with Bu3SnH or Ph3SnH (15 equivalents), which allows the reductive decomplexation to be handled at 0 oC.106 Thus, as presented in Scheme 1.29, the use of the latter modified condition furnished the successful formation of one isomer (no decomposition) as well as no over-reduction was observed.

(OC)6Co2 H H H O n-Bu3SnH, benzene H O I O O H o H 65 C, 81 %

Scheme 1.29: Tributyltin hydride decomplexation.

To address the above isomerization/over-reduction problem the

102 Et3SiH/bis(trimethylsilyl)ethyne (BTMSA) is also often employed. The BTMSA is essentially a Co2(CO)6 scavenging alkyne, and the resultant triethylsilanyl alkene can later be converted into the desired alkene in the presence of trifluoroacetic acid (TFA)105,107

(Scheme 1.30). This method may also successfully be applied to acyclic alkynedicobalt complexes. However, mixtures of alkenylsilanes sometimes result, the result of a regioselectivity issue, even though there is a direct trend toward the main isomeric product being functionalized with silicon a- to an electron-withdrawing group (as will be

35 mentioned later) or on the less-sterically crowded carbon. The regioselectivity is improved in the reaction of alkyne-Co2(CO)4(dppm) complexes, as opposed to the alkyne-Co2(CO)6 complexes.108 Reductive decomplexation may thus give the framework of the preparation of various natural products, when a medium-sized ring is critical.

H H H H H H Et SiH (5 equiv) O O O O 3 OH OH H H H H Me Si SiMe (2 equiv) 3 3 O O Co2(CO)6 o BnO H BnO H DCE, 60 C, 2 h, 94 % H OBn SiEt3 H OBn

Scheme 1.30: Hydrosilation of dicobalthexacarbonyl moiety using triethylsilane.

Scheme 1.31 illustrates a useful version of the above method employing Et3SiH- based hydrosilylation in tandem with acid-induced protodesilylation, to give the alkene.89,91

The process normally gives overall good to excellent yields of the reduction product. In a complementary manner, the corresponding hydrosilylation/fluorode- desilylation method is also effective for similar transformations.109

OMe OMe MeO MeO

MeO 1) Et3SiH (5 equiv) MeO MeO MeO MeO Me3Si SiMe3 (2 equiv) MeO DCE, 80 oC Co2(CO)6 MeO 2) TFA, 95 % MeO

Scheme 1.31: Hydrosilylation/protodesilylation of alkynedicobalt hexacarbonyl complex.

36 Another practical protocol for reductive decomplexations of alkynedicobalt complexes is sodium hypophosphite (NaH2PO2•H2O) in 2-methoxyethanol (Scheme

1.32).110 This condition also provides the alkenes in good yields. Although hypophosphite can produce over-reduction of cycloalkynone complexes to cycloalkanones, this tendency

89,111 is less than the over-reduction with Bu3SnH.

Ph Ph H BnO NaH2PO2 H2O (5 equiv) H O BnO O OH o MeO MeO 65 C O MeO O n Co2(CO)6 H H n n = 1-3

Scheme 1.32: Sodium hypophosphite decomplexation.

1.6 PERICYCLIC REACTIONS

Pericyclic reactions are types of chemical reaction often considered to be the most effective and best realized chemical transformations available to the organic synthetic chemist, due to high levels of regio-, chemo-, and diastereoselectivity normally available.

Therefore, pericyclic reactions have been used for the synthesis of many complex ring systems. The defining feature of pericyclic reactions is that the construction of the products occurs as a result of starting material conversion through a cyclic reaction transition state.

Unlike most chemical transformations, pericyclic reactions do not involve any intermediates (Scheme 1.33).112

Scheme 1.33: Cyclic transition state example of a pericyclic reaction.

The five main categories of pericyclic reactions are as follows: cycloadditions, electrocyclizations, sigmatropic rearrangements, chelotropic reactions, and group-transfer reactions (Scheme 1.34). Cycloaddition products are formed as a result of two or more s- bond formations between the termini of two or more conjugated systems. On the other hand, electrocyclization reactions involve the formation of one s-bond between the termini of a conjugated system, and sigmatropic rearrangements involve the conversion of one s- bond into another s-bond as a substituent migrates across a p-system. Chelotropic reactions result from the conversion of a lone pair and a p-bond into two s-bonds. Group-transfer reactions involve the conversion of one p-bond into one s-bond or the transfer of a group of atoms from one molecule to another. Scheme 1.34 gives a representative example of each reaction type.

38 a) Cycloaddition (i.e., Diels-Alder reaction)

O OMe O OMe H heat or

BF OEt OTMS 3 2 OTMS H O O

b) Electrocyclization c) Sigmatropic Rearrangement (i.e., 6π electrocyclization) (i.e. Cope rearrangement)

heat heat

d) Cheletropic Reaction e) Group Transfer Reaction (i.e., Simmons-Smith reaction) (i.e., ene reaction)

Zn-Cu heat CH2I2

Scheme 1.34: The five sub-divisions of pericyclic reactions.

Many pericyclic reactions have been developed to favour a high degree of enantioselectivity with the introduction of chiral catalysts. Therefore, pericyclic reactions tend to have a critical role in the synthesis of complex natural products.

1.7 THE NAZAROV CYCLIZATION REACTION

The Nazarov reaction is a pericyclic reaction that involves the formation of five- membered rings as a result of 4p electrocyclizations that classically yields cyclopent-2- enones from divinyl ketones as starting materials (Scheme 1.35).113-117 The traditional mechanism of the Nazarov reaction is initiated by a presence of a Brønsted or Lewis acid, forming a pentadienyl cation (1.41), that typically undergoes ring closure to form an

39 oxyallyl carbocation (1.42) through the 4p electrocyclization. In the simplest version, the latter intermediate then undergoes proton transfer (elimination) to yield a five-membered ring, cyclopent-2-enone (1.43).

LA LA O O O Lewis Acid =

1.41

LA LA O O O H

H 1.43 1.42

Scheme 1.35: Mechanism of the classical Nazarov reaction.

1.7.1 STEREOSELECTIVITY IN THE NAZAROV REACTION

The ring closure step for the Nazarov reaction is diastereospecific and is controlled by Woodward-Hoffman rules. Following the initiation step by an acid catalyst (thermally), continuity of the phase overlap from the HOMO dominates, and therefore the substituents at both termini, rotate in the same direction (conrotatory) (Scheme 1.36a). However, when the reaction undergoes photochemical induction, the SOMO (generated from the promotion of a HOMO electron to the LUMO) dominates, thus the substituents at both termini rotate in opposite directions (disrotatory), as shown in Scheme 1.36b.112

40 a) Acid initiated cyclization LA LA O O conrotatory

b) Light initiated cyclization LA LA O O disrotatory

Scheme 1.36: Diastereospecificity in the Nazarov cyclization for both (a) thermal and (b) photochemical processes.

Another feature of the electrocyclization step is that it can proceed in either a clockwise or counterclockwise manner (known as torquoselectivity), producing an unequal mixture of enantiomers. Many efforts have been dedicated towards the achievement of an enantioselective Nazarov cyclization using chiral Lewis acids that give high torquoselectivity to form a single and selected enantiomer. A representative case is shown below (Scheme 1.37).118

2- O O SBF6 N N N O O Cu O O Ph Ph OEt OEt CH2Cl2,, RT Ph Ph Ph Ph 98 % (86 % ee)

Scheme 1.37: Enantioselective Nazarov cyclization promoted by a chiral Lewis acid.

41 1.7.2 REGIOSELECTIVITY IN THE NAZAROV REACTION

A drawback of the Nazarov cyclization reaction is that the regioselectivity of the proton elimination step is poor, generating a mixture of products in some cases (Scheme

1.38).

O OH

acid - H

O O O O

Scheme 1.38: Nazarov reactions giving non-regioselective proton elimination.

Denmark and co-workers119 reported a general solution to overcome this problem by the introduction of the trialkylsilyl group, ensuring the controlled collapse of the cyclopentadienyl cation due to the stabilization related to the positive charge becoming b- to the silicon atom (b-stabilization effect), as shown in Scheme 1.39.120

O TBS OH O regioselective CF3COOH SiMe2Ph elimination

β-stabilization 75%

Scheme 1.39: Silicon-directed Nazarov reactions giving regioselective elimination.

42 Recently, Ichikawa and co-workers,121 following the achievement of the silicon- directed Nazarov cyclization, have established a fluorine-directed Nazarov cyclization, taking the advantage of the b-destabilization of a positive charge by fluorine atoms, ensuring regioselective elimination (Scheme 1.40).122

O OTMS O CF3 regioselective TMSOTf elimination CF3 CF3

95% β-destabilization

Scheme 1.40: Fluorine-directed Nazarov reactions to give regioselective elimination.

1.7.3 STERIC INFLUENCE OF a-SUBSTITUENTS IN THE

NAZAROV REACTION

An increase of the cyclization efficiency in the Nazarov reaction can be accomplished by introducing one or more alkyl substituents a- to the carbonyl group

(Figure 1.6).113-117

s-trans/s-trans s-trans/s-cis s-cis/s-cis O O O

R1 R2 R1

R2 R1 R2

R1, R2 = alkyl R1 = alkyl, R2 = H R1, R2 = H

decreasing Nazarov reactivity

Figure 1.6: Nazarov reactivity increase with a-substitution.

43 As mentioned above, the main feature of the Nazarov cyclization, in particular, is the formation of the pentadienyl cation, following by the electrocyclization ring closure to an oxyallyl cation. Thus, for a better achievement for this transformation, the starting material must spend much of its time in the s-trans/s-trans conformation, thereby placing the vinyl groups in an appropriate orientation. However, when there are no a-substituents, the divinyl ketone prefers an s-cis/s-cis conformation in order to minimize steric interactions between the two sets of methylene protons. Typically, a-substituted substrates influence the reaction rate and the efficiency of the ring closure step favourably, due to an allylic strain-based increase in the percentage composition of s-trans conformers.

1.7.4 THE POLARIZED NAZAROV REACTION

The reaction rate of the Nazarov reaction also is affected by electronic factors.

Frontier and co-workers have demonstrated that by designing divinyl ketones to contain one electron-rich double bond (vinyl nucleophile) and one electron-poor double bond

(vinyl electrophile), a “push/pull” mechanism is allowed (Scheme 1.41).123,124

O O (TfO)2Cu O O O O O Cu(OTf) O OMe 2 OMe O OMe o 55 C, 2 h δ− δ+

> 99%

Scheme 1.41: Rationale behind the design of the polarized Nazarov reaction.

44 A tremendous acceleration in the reaction rate with such polarized substrates has been noted by Frontier and co-workers; in some case only a two-hour reaction time was required to affect the quantitative conversion of substrates using a mild Lewis acid such as

Cu(OTf)2. The elimination step also was regioselective, regenerating the “nucleophilic” double bond because of the stabilization of the a-positive charge by the electron donating group. In addition, the addition of only one electron-donating or electron-withdrawing group (EDG or EWG, respectively) at either a-position was important for good reactivity, even though the addition of the electron-rich 2, 4, 6-trimethoxyphenyl (TMP) at one b- position was required for the highest yields (Scheme 1.42).123,124

X R1

Cu(OTf) Cu(OTf)2 R2 2

α-EDG α-EWG X = O, R1 = H X = CH2, R1 = COOMe O O

X R1 X R1

R2 R2 R2 = Cy (60 %, 0.5 h) R2 = Cy (70 %, 14 h) R = TMP (86 %, 0.25 h) R2 = TMP (86 %, 0.33 h) 2

Scheme 1.42: The polarized Nazarov reaction with only one “polar” a-substituent.

1.7.5 THE NAZAROV REACTION OF ALLENYL VINYL KETONES

The first report representing the replacement of one of the alkenes of a divinyl ketone by an allene was published by Hashim group. A significant rate enhancement was

45 observed, such that allenyl vinyl ketones underwent Nazarov cyclization spontaneously during silica gel chromatography, to produce the corresponding exo- methylene cyclopent-

2-enones (1.44) (Scheme 1.43).125

OH O O O Ph Ph Ph DMP SiO2 Ph C

54% 1.44

Scheme 1.43: The Nazarov cyclization of allenyl vinyl ketones.

There are two related reasons for the increase in reactivity of allenyl vinyl ketones relative to their divinyl ketone analogues. First, it is as a result of the alleviation of the allenic strain in the transition state upon generation of allyl cation. The second reason is conformational in nature; the preferred conformation for most of these molecules is the reactive s-trans that is required for the Nazarov cyclization, where the steric interaction between vinyl hydrogens would be minimized (Figure 1.7).113

s-trans/s-cis s-trans/s-trans s-cis/s-cis s-trans/s-cis O O O O H C H H H VS. H C H Ph H Ph H Ph H H H Ph H

Figure 1.7: The steric rationale behind increased reactivity of allenyl ketones.

46 1.7.6 NAZAROV REACTION OF AROMATIC SUBSTRATES

Further study showed that aryl vinyl ketone substrates can be used for the Nazarov reactions. In order to achieve the electrocyclization, the aromaticity of the molecule must be lost, and it is restored following the proton elimination step (Scheme 1.44). However, this often requires harsh reaction conditions to temporarily destroy the molecule's aromaticity. While the rearomatization step makes it difficult to impossible to determine whether the reaction is truly a conrotatory electrocyclization, it is widely accepted as a

Nazarov reaction.

A O O O Acid

electrocyclization aromatic non-aromatic aromatic

Scheme 1.44: Nazarov reaction of aryl vinyl ketone.

Specific example includes the synthesis of indanones, which has been reported by

Ohawada and co-workers.126 This reaction was initiated by the addition of trifluoromethanesulfonic acid (CF3SO3H) to the Nazarov precursor, aryl vinyl ketone, at low temperature, forming the desired five-membered ring (Scheme 1.45).

47 O O Ph CF3SO3H Ph 0 oC, 5 h 98 %

Scheme 1.45: Nazarov reaction of aryl vinyl ketone to produce an indanone.

West and coworkers127 reported the Nazarov reaction-based synthesis of oxazolidinone-substituted aryl vinyl ketones (1.48) from aryl aldehydes (1.46) and lithiated allenamide (1.45), as shown in Scheme 1.46. They assumed that the presence of the a- amido group would polarize the pentadienyl cation intermediate and increase the efficiency of the cyclization. The treatment of the aryl vinyl ketones (1.47) with Lewis acids such as

Eu(OTf)3 and FeCl3 only gave back starting material. However, indium (III) triflate was found to be efficient Lewis acid for promoting the electrocyclization product, but it worked with a naphthalene derivative only. Eventually, when the aryl vinyl ketones was treated with triflic acid, the Nazarov cyclization products were formed in excellent yield in most cases.

48 O O O O O N O THF, -78 oC to RT N Li H Me C 1.47 (65 %) 1.45 1.46

O O CF SO H, 65 oC O 3 3 N

Me 1.48 (98 %)

Scheme 1.46: Nazarov reaction to produce oxazolidinone-substituted aryl vinyl ketones.

1.7.7 THE INTERRUPTED NAZAROV REACTION

It is well understood that the classical Nazarov mechanism involves the loss of a proton from the oxyallyl cation intermediate to generate enolic cyclopentadiene, which further tautomerizes to give the final cyclopentanone product. However, West and co- workers128 have extensively studied what they term the "interrupted Nazarov reaction", in which there is an additional p-system or nucleophile to attack the oxyallyl cation intermediate (Scheme 1.47). The interrupted Nazarov products have three new stereocenters instead of only one, which is a synthetically useful development.

49 SiMe H H 3 H SiMe SiMe3 3

O Cl O OTiCl3 Cl-TiCl3 Cl: 31%

Scheme 1.47: The interrupted Nazarov reaction.

As shown in the above scheme, the source of the nucleophile can be from the acid itself, or it can be present in the reaction medium. Alkenes,129-132 arenes,133,134 halides,135 and hydride136 have been used successfully as nucleophiles that have been used. It has even been confirmed by West that an intramolecular cascade process including internal alkenes can be initiated by the oxyallyl cation to form a complex ring system (Scheme 1.48).137a

The desired product here shows new six stereocenters, that have been generated diastereoselectively in one pot. A recent study also reported a catalytic asymmetric interrupted Nazarov-type using 2-indolylmethanols and cyclic enaminones as nucleophiles.137b

Cl4Ti O O

TiCl4

-78 oC, 5 min O

Scheme 1.48: An intramolecular interrupted Nazarov reaction.

50 1.7.8 ISO-NAZAROV

The iso-Nazarov reaction is another variant of Nazarov reaction, which is mechanistically very similar to classical Nazarov as it involves a 4πe- conrotatory electrocyclization, but which differs in outcomes due to substrate variability, as in α,β,γ,δ- unsaturated carbonyl compounds, include dienals and dienyl-ketones (Scheme 1.49).

Initially, it was termed as anomalous Nazarov reaction by Denmark in 1988,138 and later renamed as the iso-Nazarov reaction by Trauner in 2003.139

A O O A O R' O 4π conrotatory R' - A R' Acid A R' electrocyclization R R R R

R' O R' O R' O R R R

Scheme 1.49: Iso-Nazarov reaction.

Interestingly, after electrocyclization through 4p conrotation, the reaction affords a cyclopentanone via a group migration. The migration ability of alkyl or aryl groups or hydride (R′) vary and can affect the ease of the formation of possible cyclopentenone products. Also, the starting dienyl carbonyl remains in equilibrium with 2H-pyran intermediate (1.49) via oxa-6π-electrocyclic reaction, which facilitates the reaction and sometimes may be trapped to provide a different product, containing a pyran system

51 (Scheme 1.50), as described by Shoji et al. in 2002.140 In this case, the 2H-pyran undergoes a Diels–Alder-type [4 + 2] cycloaddition to give the natural product epoxyquinol A (1.50) stereoselectively.

O O OH OH OH [4+2] HO O O O O O Me Me O + isomer O O Me Me O (25%) (40%) 1.49 1.50

Scheme 1.50: 2H-pyran intermediate trapping.

The first example of the iso-Nazarov reaction was reported by Märkl et al. in

141 1962, using a dienoic acid chlorides and AlCl3 (Lewis acid), which promoted the isomerization of 1.51 and 1.52 to obtain 2-cyclopentenone (1.53) as depicted in Scheme

1.51. Several other substrates were utilized to transform them into their respective five- membered cyclic scaffolds, but the chemistry was not fully explored due to the strict structural requirements of a cis-dienal in order for ready conversion to these products to occur. In contrast, their trans-isomers, whose synthesis is quite easy due to thermodynamic stability, have not been found to undergo the iso-Nazarov.

52 O Cl O Cl Cl Ph AlCl , CS Cl AlCl , CH Cl Cl Cl 3 2 3 2 2 O Cl Cl Cl Ph Cl Cl Cl Cl Cl Cl Ph 1.51 1.53 1.52

Scheme 1.51: First example of iso-Nazarov to afford a 2-cyclopentenone.

In 1982, Denmark et al.119 reported the use of silicon substituted divinyl ketone

(1.54), which was transformed to a cyclopentenone via an FeCl3 promoted cyclization

(Scheme 1.52). It was proposed that the mechanism of reaction involves hydroxy- pentadienyl cation (1.55), which undergoes cyclization followed by 1,2-migration to afford final product 1.56; this proposal was supported by 13C labeled substrate 1.54*, which transformed to the product 1.56*. Several other Lewis acids also were reported as being useful in the iso-Nazarov reaction, including Me2AlCl, p-TSA, MnO2, PtCl2, Cu(OTf)2, triflic acid, and a Au(I) catalyst.

SiMe3 SiMe3 O FeCl 3 FeCl FeCl3 O 3 O ∗ ∗ SiMe3 ∗ 1.54 1.55

SiMe3 O

∗

1.56

Scheme 1.52: Silicon directed iso-Nazarov reaction.

53 Domino or cascade reactions have been defined and reviewed by Tietze,142 as ones which involve two or more bond forming and breaking reactions consecutively without additional reagents. Therefore, they afford more molecular complexity in relatively simple and environmentally benign processes.

A domino- cascade reaction has been reported by Shudo,143 involving a triflic acid promoted iso-Nazarov-type cyclization/arene trapping reaction with cinnamaldehydes or with chalcones (1.57) to afford the respective phenyl-indenes (1.58 and /or 1.59) (Scheme

1.53a). An additional domino reaction involving an iso-Nazarov using a Pt(II) catalysis, was reported by Sarpong,144 leading to the formation of cyclopentenones (1.61) through rearrangement of epoxy-propargylic esters (1.60; Scheme 1.53b). Other variants include a named reaction, the Piancatelli reaction,145 which is an acid catalyzed rearrangement reaction of 2-furylcarbinols to 4-hydroxycyclopentenones.

a) O Ph Ph TfOH benzene R and/or OH R R R 1.57 1.58 1.59

b) O

R4 O O R O R PtCl2 (0.1 equiv) 3 5 R3 R R PhMe, 100 oC 5 4 R2 O

R2 R1 O R1 H 1.60 1.61

Scheme 1.53: Domino or cascade iso-Nazarov reaction.

54 1.7.9 HOMO-NAZAROV REACTION

As outlined previously, the Nazarov cyclization was discovered to prepare cyclopentenones with the help of a stoichiometric or catalytic Lewis or protic acids. The reaction proceeds through electrocyclic ring closure of a pentadienyl cation followed by proton transfer (Scheme 1.54a).146

It would be a worthy development to find a way to access larger ring systems via the concepts involved in the Nazarov reaction. The ability to afford only five- membered ring systems is something of a limitation. As opposed to the divinyl ketones involved in the basic process, replacing one of the vinyl groups by a cyclopropane leads to a new class of Nazarov reaction known as the formal homo-Nazarov reaction. The latter process has great potential for the synthesis of cyclohexenones, a six-membered ring system (Scheme

1.54b).

O O O O R1 R2 R R R R R1 R2 a) Nazarov 1 2 b) Homo-Nazarov 1 2 vs

R3 R4 R R R3 R3 R4 3 4 R4

Scheme 1.54: Classical Nazarov reaction (a) versus homo-Nazarov (b).

Unlike the classical Nazarov reaction, the homo-Nazarov initially required harsh reaction conditions, like polyphosphoric acid at 80°C leading to multiple products,147 or

148 multiple equivalents of SnCl4 at 80°C, leading to multiple products and limiting the extensive use of this reaction type. However, Waser and co-workers149 recently reported

55 the first catalytic method of the homo-Nazarov reaction for the cyclization of vinyl- cyclopropyl ketones (Scheme 1.55).

O O TsOH H O (20 mol%) O 2 O

CH CN, 70 % Ar 3 Ar 1.62 1.63

Scheme 1.55: Homo-Nazarov reaction for the cyclization of vinyl-cyclopropyl ketones.

Non-aromatic substrates have been used to the production of valuable polycyclic cyclohexenones at room temperature as well as serving as opening experiments for investigating the reaction mechanism. A dihydropyran-derived substrate (1.62) was prepared via a Corey-Chaykovsky cyclopropanation. The cyclization step was achieved using 20 mol% of toluenesulfonic (TsOH) acid at room temperature, leading to the formation of the desired product, cyclohexanone (1.63) in excellent yield (Scheme 1.55).

This reaction is mechanistically different from the classical Nazarov, as the investigation seems to indicate a stepwise mechanism with a rate-limiting cyclopropane ring opening, as depicted in Scheme 1.56, where the cyclopropane opening leads to the formation of a carbocation at the β- site to the carbonyl. Later, nucleophilic attack by the vinyl group leads to the formation of the six-membered ring intermediate, generally facilitated by an electron donating group (EDG).

56 EDG = electron donating group LA = Lewis acid

Scheme 1.56: Mechanism of formal homo –Nazarov reaction.

The effect of an electron-donating aromatic group b- to the carbonyl on the cyclopropane was examined, and has a profound influence. In fact, the presence of this electron donating group was necessary for the formation of cyclohexanone products; its absence led to reaction failure. Specifically, this means that electron-rich aromatic groups at R3 favoured the reaction. Also observed was the effect of a polar solvent like acetonitrile, which assisted in affording a good yield of the product by lowering the polymerization side reaction. The reaction has limitations that no asymmetric induction was obtained, even after using chiral Brønsted or Lewis acids.

In order to overcome the above limitations of catalytic formal homo-Nazarov reaction mediated by TsOH•H2O, the same research group reported an extensive study in

2011.150 Two different strategies involving activated cyclopropanes were used (Figure

57 1.8). Strategy 1 included the introduction of an electron withdrawing group (EWG) α- to carbonyl, such as an ester on the cyclopropane ring, whereas strategy 2 involved electron donating group (EDG) incorporation β- to carbonyl on the cyclopropane ring (i.e. an amide or ether). Both the strategies allow further polarization of the three-membered ring of vinyl- cyclopropyl ketones.

Figure 1.8: Two strategies for homo-Nazarov reaction.

The first strategy leads to increasing the reactivity tenfold which allows expanding the reaction to allow non-electron-rich aryl donor substituents at the β- position. Compared to TsOH, other Lewis acid catalysts like Ni(ClO4)2•6H2O, and BF3•Et2O were found to successfully afford the products in good yield (Scheme 1.57), even in presence of a chloro substituent at benzene ring. It also assisted in asymmetric induction, accomplished by employing chiral Lewis acid catalysts (Scheme 1.58).

58 O O O CO2Me O CO Me 2 Catalyst

Solvent

Catalyst Solvent %conv (R)

TsOH (20 mol%) CH3CN 0 (OMe) Ni(ClO4)2 6H2O (20 mol%) CH2Cl2 100 (H) BF Et O (50 mol%) 3 2 CH2Cl2 100 (H), 85 (Cl)

Scheme 1.57: Formal homo-Nazarov reaction for non-electron-rich aryl substituents.

O O O CO2R O CO R 2 1) Mgl2 (28 mol%), Ligand (30 mol%), DCM, MS 4A, RT *

2) NaCl, THF, (R = Me) or TFA, DCM, RT (R = tBu) OMe OMe

R Ligand ee% O O Me A 11 N tBu A 25 N N iPr A iPr

Scheme 1.58: Formal enantioselective homo-Nazarov reaction for electron-rich aryl substituents.

In the second strategy, an amide or ether at the β- position, especially the former, lead to heterocyclization effectively when indole heterocycles were used instead of vinyl groups (Scheme 1.59). This reaction has found particular utility in the synthesis of natural

59 alkaloids. With the help of a copper(II) Lewis acid catalyst, a regio- and stereoselective cyclization reaction on the C3- position of the indole was favoured. Conversely, TsOH (a

Brønsted acid) in a nonpolar solvent favored C-N bond formation at the N1 position.

Cbz H O N

HN Cu(OTf)2 H TsOH, DCM, RT, 15 min CH3CN, RT 15 min. 80 % 85 % Cbz O N H Et Et HN H Cu(OTf)2, CH3CN, RT N O N 48h, 90% Cbz B A

Catalyst Solvent A : B

TsOH CH3CN 1.6 : 1 Cu(OTf) CH CN 7 : 1 2 3 1 : 21 TsOH DCM

Scheme 1.59: β-Heteroatom substituent mediated formal homo-Nazarov cyclization.

1.7.10 CROSS-CONJUGATED TRIENES-VINYLOGOUS NAZAROV

REACTIONS

In the most common form of the Nazarov reaction, it is a carbonyl at C-3 position of a cross-conjugated dienone that is activated with Lewis acid. In 2009, West and co- workers151 reported the first example of a vinylogous Nazarov reaction, in which a cross-

60 conjugated triene undergoes cyclization (Scheme 1.60). For this vinylogous Nazarov reaction, the carbonyl group of dienone is replaced by an electron-deﬁcient alkene at C-3 to give the cross-conjugated triene, so that capability of activation would remain at that C-

3 site for the purpose of cyclization. The vinylogous Nazarov precursor, a trienoate or related carbonyl, was then treated by a stoichiometric (TiCl4) or catalytic (Sc(OTf)3) Lewis acid, generating conjugated alkylidenecyclopentenes by the vinylogous Nazarov cyclization. This new methodology was reported to be amenable to amides, esters, aldehydes, and ketones, each forming the desired cyclization product in good yields.

Scheme 1.61 outlines the probable mechanism for this reaction.151

CO Et O 2 1) Li OEt

2) 5 mol% VO(acac)2 iPr iPr o iPr iPr PhCH3, 80 C

CO2Et o TiCl4, DCM, - 78 C to RT OR

Sc(OTf) , DCE, 55 oC, 24 h 3(cat) iPr iPr

Scheme 1.60: Cyclization of cross-conjugated trienes via vinylogous Nazarov cyclization.

61 LA LA O O O

OEt OEt

LA 4π electrocyclization iPr iPr iPr iPr iPr iPr

β-elimination

and H+ transfer

iPr iPr

Scheme 1.61: Proposed mechanism for the vinylogous Nazarov reaction.

1.7.11 THE NAZAROV REACTION OF UNSATURATED a-

DIKETONES

In 2011, Frontier and co-workers152 reported the ability to access pentadienyl cations through a conjugate addition onto dienyl diketones (Scheme 1.62). A broad range of amine and malonate nucleophiles were found to attack the dienyl diketones via 1,6- conjugate addition upon the addition of a catalytic amount of the mild Lewis acid

Yb(OTf)3. Following complexation of the Lewis acid with adjacent ketone, the formation of a pentadienyl cation results, and the system underwent Nazarov reactions, forming hydroxy-cyclopentenones (1.64).

62 YL n O O O O O R2 R Y(OTf)3 1 mol% R1 1 HO R R2 2 Et3N, LiCl R1 THF, RT, Nu Nu Nu 1.64

Scheme 1.62: Frontier MO study of vinylogous Nazarov cyclization.

1.8 SYNTHETIC APPLICATIONS OF THE NAZAROV

CYCLIZATION

The challenge in any designed synthetic method is found by its ability to be applied in the formation of complex natural products.153,154 Therefore, the following sections very selectivity demonstrate a few examples of the application of the Nazarov reaction.

1.8.1 USE OF THE “CLASSICAL” NAZAROV REACTION IN

SYNTHESIS

The natural product racemic trichodiene was synthesized in 1990 by Harding and co-workers,153b via the Nazarov reaction as a major step. The main reason for selection of the Nazarov reaction is that the natural product contains two adjacent quaternary stereocenters, thus the diastereospecific character of the Nazarov reaction would guarantee the necessary trans relationship selectivity (Scheme 1.63).

63 O O H H O BF3 OEt2 H H (10 equiv)

CHCl3, reﬂux 2.4 : 1 H2O, 89 %

(+/-)-trichodiene

Scheme 1.63: Synthetic route to racemic trchodiene.

1.8.2 USE OF THE “POLARIZED” NAZAROV REACTION IN

SYNTHESIS

It has been demonstrated that the roseophilin has activity against K562 human erythroid leukemia cells and human nasopharyngeal carcinoma cells, and therefore is an important synthetic target. Frontier and co-workers154 established an approach to the formal synthesis of racemic roseophilin via macrotricycle (1.67), through a scandium(III)- catalyzed Nazarov cyclization of polarized aryl vinyl ketone (1.65) (Scheme 1.64).

The divinyl ketone 1.65 is capto-datively substituted at the a- and b-positions, respectively, relative to the carbonyl group. Together, they tend to enhance reactivity greatly, and give better selectivity for reaction. The presence of polarized groups at both

C-2 and C-4 positions labelled on the structure was particularly effective in the cyclization of the pentadienyl cation. The vinyl group substituted by the methoxycarbonyl is undoubtedly the electron poor site (electron withdrawing), whereas the one with pyrrole moiety is the relativly electron rich site (electron donating).

64 The product of the Nazarov cyclization 1.66, was the macrocyclization precursor.

This macrocyclization was then carried out using dilute and controlled conditions on the acetate of 1.66, via p-allyl palladium catalysis.

acceptor donor OTBS MeOOC 1 5 5 Sc(OTf)3 (10 mol%) MeO 3 O 2 4 N N Ts LiClO , 80 oC, DCE Ts 5 OTBS O O 4 1.65 65% 1.66

N MeO N O H (+/-)-roseophilin O 1.67 NH Cl

Scheme 1.64: Total synthesis of racemic roseophilin.

1.9 NEW DIRECTIONS OF THE NAZAROV CYCLIZATION

REACTION

As mentioned above, Nazarov cyclization has become an essential strategy in organic chemistry. In addition of variable Lewis acid catalysts, photochemical conditions for cyclization have been studied for this type of reaction. A new class of the Nazarov reaction will be discussed, involving the formation of a seven-membered ring, as opposed to a five-membered ring. However, by the date our studies started there were no examples

65 of seven-membered ring construction reported by vinylogous Nazarov reactions at all, and to this date still no thermal ones.

Opatz and co-workers155 reported the first example of photochemistry to induce a vinylogous Nazarov reaction producing a seven-membered ring, cycloheptadienone core.

This reaction is a one-pot cascade reaction based on three steps: (i) a photochemical isoxazole-azirine ring contraction, (ii) cobalt(II)-catalyzed ring expansion, and (iii) the photochemical 6p-electrocyclic vinylogous Nazarov reaction (Scheme 1.65).

N O X acetylacetone X Co(acac)2 Ac

CH2Cl2, hv, RT N Me 1.68 O H

X = CH=CH, O, S X hv in situ Ac

N Me O H

Scheme 1.65: One-pot photochemical isomerization-condensation-photocyclization cascade.

In this case, no Lewis acid or any metal catalyst seems to be needed. Particularly, if the compound 1.68 was treated with BF3•OEt2 in dichloromethane, no cyclization could be observed. Opatz reported that a thermal disrotatory electrocyclization (since it is a 6p photochemical condition) would demand an unfavourable shape of the p system with a minimized degree of conjugation, and thus involve a high energy barrier. The following

66 scheme presents the proposed mechanism for the seven-membered ring formation via the light-induced Nazarov reaction (Scheme 1.66).155

X H X hv Ac in situ Ac 6π electrocyclization N Me N Me O H O H

X + + - H , + H Ac

H N Me O H

Scheme 1.66: Proposed reaction mechanism for 6p light-induced Nazarov reaction.

67 1.10 RESEARCH OBJECTIVE

Although there are extensive studies of the well-known Nazarov cyclization reaction of dienones, and a few examples known of vinylogous Nazarov reactions to form five- membered ring systems, the formation of a seven- membered ring system through a thermal vinylogous Nazarov is unknown. As outlined above, the homo-Nazarov capability to extend the ring size of Nazarov reactions is important, and it is worth looking for a way to access larger ring systems via the concepts involved in the “vinylogous” approach of

West and co-workers.151 It is desired that the introduction of an electron-deficient dienyone moiety (1.69) might allow the formation of the seven-membered ring systems (Scheme

1.67a). In this research, investigation whether the alkynedicobalt function (1.70) insulates the organic carbonyl from the distal p-system sufficiently to allow it to be the electron rich unit, to cyclize with electron deficient enone was carried out (Scheme 1.67b).

a) O O

+ R3 H OR L.A. R3 R1 R1 R4 R4 R2 R2 1.69 b) (OC) Co 6 2 O (OC)6Co2 O

+ R3 H OR L.A. R3 R1 R1 R4 R4 R2 R2 1.70 Scheme 1.67: Proposed mode of cyclization by vinylogous Nazarov cyclization.

68 CHAPTER 2 RESULTS AND DISCUSSION: METAL-MEDIATED

VINYLOGOUS NAZAROV REACTIONS

2.1 RETROSYNTHETIC ANALYSIS

Despite the extensive body of Nazarov reactions, and the more modest number of vinylogous Nazarov reactions, to afford five-membered ring system, the formation of seven-membered ring systems via thermal vinylogous (or acid induced) Nazarov reactions remains elusive (Scheme 1.67). Having established previously the ability of alkyne-

156 Co2(CO)6 units to allow g-carbonyl cation formation, it is proposed that the alkynedicobalt function insulates the electron-withdrawing nature of the organic carbonyl from the distal p-system sufficiently to allow it to participate in vinylogous Nazarov reactions with electron deficient enones and their analogues. This would be a significant development in synthetic methodology, owing to the limitation of methodologies that provide the thermal access to the seven-membered system version of the Nazarov cyclization reactions.

The first aim here was to design precursors for the vinylogous Nazarov reactions, and then study the cyclization under acidic conditions. The first group of attempts involved of a carbocyclic arene moiety with electron-donating groups to react with the enone unit.

Electron donating groups (EDG) favour the cyclization because through electron donation they tend to increase the arene nucleophilicity. DFT calculations have been conducted to examine the impact of the electron donating group (OMe) on the ring closure step. We calculated reaction barriers and thermodynamics for the ring closure of the protonated

69 starting material of A (with a phenyl group) and B (with a 3-methoxyphenyl group) at B88-

PW91/dzvp basis set (Scigress Explorer, CACheÒ) (see Appendix). The results obtained predict that introducing methoxy group para- to the most nucleophilic carbon would lower the cyclization barrier by 9.6 kcal/mol (Scheme 2.1). It is also worth noting that the vinylogous Nazarov cyclization itself would be more energetically favorable by 15.6 kcal/mol. Thus, cyclization using an electron donating group para- or ortho- to the nucleophilic carbon might be more kinetically accessible and more thermodynamically favorable in comparison to the cyclization with an unfunctionalized benzene.

H Co2(CO)6 O (OC)6Co2 OH DG = 14.4a H DG‡ = 16.8a A A'

H O Co2(CO)6 (OC)6Co2 O O OH

DG = -1.2a H DG‡ = 7.2a B B'

Scheme 2.1: DFT results for the vinylogous Nazarov cyclization reactions of phenyl- and 3-methoxyphenyl cationic intermediates at the B88-PW91/dzvp level. a (kcal/mol).

The retrosynthetic approach followed to prepare and design the precursors is shown in Scheme 2.2. The key step involves forming the a,b-unsaturated ketone with an alkyne-

70 Co2(CO)6 moiety (cross-conjugated dienynone), which is then perceived to be the direct precursor to the intended product.

O O OH (OC)6Co2 R1 R1 R1

EDG R2 EDG R2 EDG R2

TMS X TMS EDG EDG EDG H

R1 = methyl, ethyl, iPr, TIPS, benzyl R2 = H, methyl EDG = OMe

Scheme 2.2: Proposed retrosynthetic method to the formation of the vinylogous Nazarov reaction precursors.

2.2 VINYLOGOUS NAZAROV CYCLIZATION REACTION

2.2.1 CARBOCYCLIC ARENE CASE

The multi-step synthesis for the first class of substitutes is outlined in Scheme 2.3 which describes the formation of the cross-conjugated a,b-unsaturated ketone for the 3- methoxyphenyl group.

71 TMS H O I O 2 equiv TMS TBAF in THF O

o Pd(PPh3)4, CuI 0 C 2.1a Et3N, THF, reﬂux 2.2a (91 %) 2.3a (79 %)

OH O

O nBuLi, THF, -78 oC O [O]

methacrolein, 0 oC CH2Cl2, RT 2.4a (50 %) 2.5a

Scheme 2.3: Synthesis of a,b-unsaturated ketone toward the vinylogous Nazarov reaction precursor.

The first step of the synthetic plan was accomplished according to the method reported by the reaction of 3-iodoanisole (2.1a) and (trimethylsilyl)acetylene (TMSA) using Sonogashira cross-coupling reaction conditions,157,158 including a palladium(0) catalyst and copper(I) iodide as co-catalyst, to produce trimethylsilyl-protected alkyne

(2.2a) in 91 % yield (Scheme 2.3). Afterward, the protected alkyne was subjected to a desilylation reaction. Even though there are various examples or conditions have been used

159 in the literature for removing the silyl group (TMS or SiMe3) from alkynes, TBAF worked reasonably well for this example, providing a good yield (79 %) for the desired alkyne 2.3a. It is worth noting that compound 2.2a and 2.3a are commercially available, albeit expensive.

The terminal alkyne (2.3a) was then deprotonated with nBuLi at low temperature (-

78 oC). Methacrolein was introduced to act as an electrophile to the nucleophilic acetylide,

72 by nucleophilic attack on the relatively electron deficient carbonyl of the methacrolein, to afford the requisite alcohol 2.4a in 50 % yield. The next step involved the oxidation of

(2.4a), to form the corresponding cross-conjugated ketone 2.5a. The initial attempt with tetrapropylammonium perruthenate (TPAP) in combination with N-methylmorpholine N- oxide (NMO), afforded the corresponding ketone (2.5a) in very low yield (28 %), without recovery of starting material. A Swern oxidation reaction was attempted;160 however, the isomeric terminal allylic alcohol was generated instead of the target ketone. Thus, we resorted to other choices of oxidation conditions, namely pyridinium dichromate (PDC) in dichloromethane at room temperature, which afforded the intended ketone (2.5a) in excellent yield (86 %). Many conditions are known for the oxidation of an alcohol to ketone, but since PDC in dichloromethane was found to be effective in the oxidation of this case, we decided to adopt these conditions for all subsequent oxidation reactions.

Table 2.1 summarizes different oxidation condition results.

73 OH O

O [O] O

Conditions

2.4a 2.5a

Entry [O] Conditions Yield

1 TPAP/NMO CH2Cl2/RT 28 %

2 Swern -78 oC to RT O OH (15 %)

3 PDC CH2Cl2/RT 86 %

Table 2.1: Oxidation reaction of alcohol 2.4a using different reaction conditions.

Having established effective conditions for the synthesis of cross-conjugated ketone, the next target was to explore the reaction’s scope on different starting materials as well as to introduce a more electron-rich moiety to the aromatic ring. Using the analogous synthetic route as the monomethoxy- system, di- and tri-methoxyphenyl substituted substrates were studied as well (Scheme 2.4).

74 TMS H O I O O 2 equiv TMS TBAF in THF R1 R1 R1 o O Pd(PPh3)4, CuI O 0 C O Et3N, THF, reﬂux

2.1b: R1= H 2.2b: R1= H (97 %) 2.3b: R1= H (90 %) 2.3c: R1= OMe

O OH

O O [O] nBuLi, THF, -78 oC

CH2Cl2, RT R1 o R1 methacrolein, 0 C O O

2.5b: R1= H 2.4b: R1= H (64 %) 2.5c: R1= OMe 2.4c: R1= OMe (56 %)

Scheme 2.4: The series of transformations to obtain cross-conjugated ketones for the di- and trimethoxy arenes.

The synthesis was initiated with a Sonogashira cross-coupling reaction of 2.1b to give 97 % of protected alkyne 2.2b, followed by the desilylation reaction afforded terminal alkyne 2.3b in excellent yield (90 %). Using nBuLi in THF as base, methacrolein and 2.3b and the commercially available terminal alkyne 2.3c, the secondary alcohols 2.4b and 2.4c were formed in 64 % and 56 % yields, respectively.

In accordance with the reaction results provided earlier in Table 2.1, the oxidation of alcohols of di- and tri- methoxyarene systems were performed via PDC in dichloromethane, afforded the corresponding ketones 2.5b and 2.5c in 87 % and 85 % yields, respectively. Alcohol (2.4b) was also oxidized using pyridinium chlorochromate

(PCC) in dichloromethane at room temperature, producing the requisite ketone (2.5b) in

75 47 % yield. It is worth mentioning that both PDC and PCC reagents are suitable for converting alcohols to ketones; however, PDC is even more effective for the oxidation of acid sensitive substrates due to it is lower acidity compared to PCC.161 The results of the oxidation reaction are summarized in Table 2.2.

OH O

O O [O]

R1 CH2Cl2, RT R1 O O

2.4b: R1= H 2.5b: R1= H 2.4c: R = OMe 1 2.5c: R1= OMe

Entry R1 [O] Product/ Yield

1 H PDC 2.5b/ 87 %

2 H PCC 2.5b/ 47 %

3 OMe PDC 2.5c/ 86 %

Table 2.2: Oxidation reaction conditions and results for di- and trimethoxy arenes.

With the successful formation of the cross-conjugated a,b-unsaturated ketones

(2.5a-c), it was now necessary to protect the alkyne. As 2.5a-c exist, the alkyne carbon b- to the carbonyl is likely reactive, and the arene ring has a substantial electron-withdrawing group present. Furthermore, any vinylogous Nazarov reaction using the 2.5a-c would form a highly unstable ring system, due to angle strain issues (Chapter 1).

76 Thus, at this point these cross-conjugated ketones were subjected to the complexation with excess dicobalt octacarbonyl (Co2(CO)8). The corresponding hexacarbonyl alkynedicobalt complexes, the suitable starting material for the vinylogous

Nazarov cyclization reaction, 2.6a, 2.6b, and 2.6c were formed in good to excellent yields

(Table 2.3).

O O (OC)6Co2 O O Co2(CO)8

R o R 1 CH2Cl2, 0 C 1 R2 R2

2.5a: R1, R2 = H 2.6a: R1, R2 = H 2.5b: R1= H, R2 = OMe 2.6b: R1= H, R2 = OMe 2.5c: R ,R = OMe 1 2 2.6c: R1,R2= OMe

Entry R1 R2 Product/ Yield

1 H H 2.6a/ 83 %

2 H OMe 2.6b/ 70 %

3 OMe OMe 2.6c/ 83 %

Table 2.3: Complexation reaction via dicobalt octacarbonyl (Co2(CO)8).

An additional advantage of dealing with cobalt complexed alkynes, in terms of practical lab work, is the ease of visualizing the characteristic colour of the alkynedicobalt moiety in the reaction mixture by TLC. All the complexes were obtained as dark red materials. Their unique and intense colour also simplified the location of complexes’ band on a chromatographic column, without UV light. Cobalt complexes are sufficiently air

77 stable that the easy purification by chromatographic methods is allowed, as well as characterization by traditional chromatography techniques (1H NMR, 13C NMR, IR, and

MS spectroscopies). However, for long-term purposes, these complexes gradually decompose in air at room temperature. Therefore, these materials must be stored at -20 oC for longer periods of time. Djurdevic (previous graduate student in Green’s group) determined that after one week storing cobalt complexes at -20 oC, decomposition of approximately 3 % was found by weight measurement and purification. The formation of the cobalt complexes was confirmed by characteristic features in IR and NMR spectroscopy. In the 13C NMR spectra, one could recognize the appearance of a broad resonance at approximately 198.4 ppm for all complexes, indicating the presence of the carbonyl carbons of the ligands on the cobalt atoms. Multiple stretching bands around 2000 cm-1 in the IR spectra also indicate the presence of C≡O ligands. Interestingly, the two vinyl protons of the enone were shown to be significantly shifted upfield, by approximately

0.3 and 0.7 ppm, in the 1H NMR spectra upon complexation, which is indicative of a shielding effect of CO ligands.

Having the cobalt complexed cross-conjugated dienynones (2.6a-c) in hand, the next step was set to attempt the thermally induced vinylogous Nazarov cyclization reaction.

An initial attempt was conducted using a common Lewis acid for Nicholas reactions, boron trifluoride diethyl etherate (BF3•OEt2). The first trial was examined with the 3-methoxy

o system (2.6a) and 3 equivalents of the BF3•OEt2 Lewis acid in dichloromethane at 0 C under N2. The progress of the reaction was monitored by TLC. After 24 h, the TLC under

UV light showed a spot had appeared below the cobalt complex initially interpreted as decomplexation of 2.6a to 2.5a. The reaction mixture was kept longer until a complete

78 starting material disappearance had occurred, at which time the starting material (2.5a) was recovered (80 %) (Scheme 2.5). The recovered (2.5a) was fully consistent spectroscopically with the samples prepared from 2.4a.

expect Co2(CO)6 3 equiv. BF .OEt O O 3 2 (OC)6Co2 O o O CH2Cl2, 0 C to RT

2.6a O

2.5a (80 %)

Scheme 2.5: Preliminary vinylogous Nazarov cyclization attempt using BF3•OEt2.

Trimethylsilyl trifluoromethanesulfonate (TMS triflate or TMSOTf) was also examined as a Lewis acid for the vinylogous Nazarov cyclization with 2.6a in

o dichloromethane at 0 C under N2. The reaction mixture was stirred overnight and monitored by TLC. Starting material was still visible on TLC, indicating that TMS triflate was not suitable Lewis acid for this system.

After these failure of conversion to the corresponding seven-membered using either

BF3•OEt2 nor TMS triflate, it was noted that many successful Nazarov cyclization had used metal based Lewis acids. Indeed, titanium tetrachloride (TiCl4) was used by West and co- workers as a Lewis acid to generate the intermediate cation in their enone based approach

79 to the vinylogous Nazarov cyclization (Scheme 1.60, Chapter 1).128 Thus, it was thought that there might be a possibility that BF3•OEt2 or TMS triflate, despite being nominally stronger Lewis acids,162 were not effective enough to drive the reaction toward the formation of the model heptatrienyl cation. As previously demonstrated in Dr. Green’s laboratory demonstrated, the use of tin tetrachloride (SnCl4) as a Lewis acid in place of

163 BF3•OEt2 can be effective in intramolecular vinylogous Nicholas reactions with arenes.

This set of reactions condition used in order to examine whether such success would be observed with SnCl4 in cyclization of 2.6a.

Gratifyingly, reaction of 2.6a proceeded with three equivalents of SnCl4 under

o analogous reaction conditions as investigated for BF3•OEt2 and TMS triflate (CH2Cl2, 0 C to RT, N2). Monitoring the progress of the reaction by TLC, exhibited the formation of new red spots below the one of the complexed starting material. After 24 hours, a full convertion of the starting material was observed with a formation of new two products.

Upon characterization, two regioisomers were detected 2.7a and 2.7a¢ in 2.2:1 ratio of para- : ortho- attachment to the electron donating methoxy group (OMe), in a combined yield of 77 %. These regioisomeric products were facilely separable by column chromatography, to afford 53 % yield of the para- (2.7a) and 24 % of the ortho- (2.7a¢)

(Scheme 2.6).

80 Co (CO) Co2(CO)6 O 2 6 (OC)6Co2 O 3 equiv. SnCl O 4 O O CH Cl , 0 oC to RT, 2 2 O 24 h

2.6a 2.7a 2.7a' para- (53 %) ortho- (24 %)

Scheme 2.6: The obtained para- 2.7a and ortho- 2.7a¢ products using SnCl4 via the vinylogous Nazarov cyclization.

The observed regiochemical selectivity is in line with the expected trends of electrophilic attack by alkoxy-substituted benzenes. Yu in 200590 demonstrated similar selectivity via an intramolecular Nicholas reaction using electron donating substituents on the benzene ring that afforded separable para-/ortho- isomers (Scheme 2.7).

Co2(CO)6 O BF3 OEt2 o OAc CH2Cl2, 0 C Co2(CO)6 Co2(CO)6 O 0.5 h O para-:ortho- 4.9:1 (53%)

Scheme 2.7: Comparable experimental regiochemical selectivity using electron rich benzene in Nicholas reactions.

The successful formation of the seven-membered ring was confirmed mainly by the

1H NMR spectra. The appearance of multiplet peaks at approximately 2.8 ppm represent the three protons at C1 and C2 (Scheme 2.8). In addition, the two singlets at d 5.81 and 5.84 ppm (vinyl protons) have disappeared upon cyclization. The majority 2.7a regioisomer was

81 evident as a singlet of Ha proton at chemical shift of 7.27 ppm. Thus, the use of SnCl4 has successfully led to the first thermally induced seven-membered ring via a vinylogous

Nazarov cyclization.

Co2(CO)6 O Ha (OC)6Co2 O O O

1 2 Para- 2.7a

O Co2(CO)6 (OC)6Co2

O O

1 2 O Ortho- 2.7a'

Scheme 2.8: The formation of two possible regioisomers.

Having optimized conditions of the metal-mediated vinylogous Nazarov cyclization reaction, attention was turned to the cases with more electron rich and symmetrical benzene derivatives, without competing cyclization regioselectivity. Di- and tri- methoxyarene systems 2.6b and 2.6c, respectively, underwent the cyclization reaction

o using the optimized reaction conditions (3 equiv SnCl4, CH2Cl2, 0 C to RT). New cyclization products, containing seven membered rings fused to benzene 2.7b and 2.7c, were prepared in 56 % and 70 % yields, respectively. The reaction results are summarized in Table 2.4.

82 O Co2(CO)6 (OC)6Co2 O O 3 equiv SnCl4 O R1 R o 1 CH2Cl2, 0 C to RT, t O O

2.6b : R1= H 2.7b : R1= H 2.6c : R = OMe 1 2.7c : R1= OMe

Entry R1 Time(t) Product/ Yield

1 H 24 h 2.7b/ 56 %

2 OMe overnight (12h) 2.7c/ 70 %

Table 2.4: Vinylogous Nazarov cyclization results using di- and tri- methoxyarene moieties.

2.2.1.1 CARBOCYCLIC ARENE SYSTEM REACTIVITY

As shown above, the role the electron-donating methoxy groups play in the cyclization is worthy of discussion. In general, the effect of multiple methoxy substituents is that of increasing the nucleophilicity of the arene. Of the three cyclization precursors

(2.6a-c), the dimethoxy- substituted 2.6b possesses the most reactive arene, whereas 2.6a contains the least reactive one. This is evidenced in the Mayr N scale, where 1,3- dimethoxybenzene (N = 2.48)164 is considerably more nucleophilic than anisole (N = -

1.18),71 and the sites of reaction in 2.6a and 2.6b ortho- or para- to a methoxy group

(Figure 2.1). On the other hand, trimethoxyaryl- substituted 2.6c contains an additional methoxy group meta- to the reactions site. The Mayr N values of 1,2,3-trimethoxybenzene

83 is unreported, but a meta- methoxy groups are slightly electron withdrawing (Hammett σ

= 0.12),165 and therefore an arene nucleophilicity in between 2.6a and 2.6c is expected.

Also noteworthy to this discussion is the fact that reasonable to assume that the rate determining step is the attack of electron rich arene on the ketone carbonyl-SnCl4 complex.166 Despite this, the rate of conversion 2.6a-c to 2.7a-c does not appear to be vastly different in the three cases. Nevertheless, with the expectation that the 3,5-dimethoxy- substituted substrates would prove to give single regioisomer further investigations were undertaken using this arene substitution pattern.

O O O

O O O 2.6a 2.6c 2.6b N = -1.18 N = unknown N = +2.48

- - less reactive Nu more reactive Nu

Figure 2.1: Proposed reactivity trend of the carbocyclic arenes system.

2.2.2 VINYLOGOUS NAZAROV CYCLIZATION REACTION: a-

SUBSTITUTED CASES

In a typical Nazarov reaction (the five-membered ring case), careful investigation of both electronic and steric effects using variety of dienones have been made. Several studies have shown the effect of electron-donating groups and electron-withdrawing groups on the rate of the electrocyclization, depending on the location of the substituent.167

84 It has been found that the electron-withdrawing groups (i.e. esters) a- to the carbonyl able to facilitate the cyclization reaction, allowing milder Lewis acids.168-170 Besides the electronic effect, steric effects using different a-substituents have a significant impact on the reactivity of a dienone, by favoring the formation of the reactive s-trans/s-trans conformation of the dienone.171 Thus, after our successful formation of the first examples of thermally induced seven-membered ring formation via the vinylogous Nazarov cyclization reaction, the next stage of this research was to explore the reaction’s scope through the study of a-substitution effects on the ring closure step. The substitutions chosen in this study were easily introduced, and they might potentially enhance the cyclization efficiency.

To obtain the appropriate precursors for the a-substitutions case, a synthetic protocol analogous to the one described earlier (when producing the precursor of monomethoxy, di-, and tri-methoxyarenes with an a-methyl group) was undertaken. The synthesis of the intended substrates was started with terminal alkyne (2.3b) by using the nBuLi and variety of aldehydes in order to generate alcohol with different a- substituents.

The reaction was proceeded successfully, affording the desired products 2.4f and 2.4d in good yields of 77 % and 82 %, respectively. However, only fair yields were obtained for

2.4e and 2.4g (Table 2.5). It is worth mentioning that all the aldehydes, except d, used in this stable are commercially available; however, they have been prepared in our lab according to the published procedures.172 The synthesized alcohols (2.4d-g) then underwent the oxidation reaction using the previously successful reaction conditions (PDC in CH2Cl2 at room temperature) to convert the alcohols to the corresponding ketones 2.5d- f in good to excellent yields (65-94 %). However, ketone 2.5g was not sufficiently pure, so

85 the yield was not calculated, and crude material was used for the following reaction step.

A summary of the results is listed in Table 2.6.

OH R O O 1) nBuLi, THF, -78 oC

2) aldehyde, 0 oC O O

2.3b 2.4d-g

Entry R Aldehyde(a-d) Product Yield

O OH

O 1 iPr a 82 %

O 2.4d

O OH

O 2 ethyl b 48 %

O 2.4e

O OH Bn 3 benzyl O 77 % c

O 2.4f

OH O TIPS Si 4 TIPS O 34 % d

O 2.4g

Table 2.5: Formation of alcohols of various a-substituted substrates.

86 OH O R R O O PDC, CH2Cl2

RT O O

2.4d-g 2.5d-g

Entry R Starting Product Product/

Material Yield

1 iPr 2.4d O 2.5d/ 93 %

2 ethyl 2.4e O 2.5e/ 94 %

O Bn 3 benzyl 2.4f O 2.5f/ 65 %

O TIPS O 4 TIPS 2.4g 2.5g/ crude material O only

Table 2.6: Formation of cross-conjugated ketones of various a-substituted substrates.

87 Having the corresponding cross-conjugated ketones (2.5d-g) in hand, the following step was the complexation reaction with an excess amount of Co2(CO)8. The desired alkyne-dicobalthexacarbonyl complexes were formed as dark red materials in good to excellent yields (69-89 %). Table 2.7 summarizes the complexation results.

O O (OC)6Co2 R R O O Co2(CO)8

o CH2Cl2, 0 C O O 2.5d-g 2.6d-g

Entry R Starting Product Product/

Material Yield

O (OC)6Co2 1 iPr 2.5d O 89 %

O 2.6d

O (OC)6Co2 2 ethyl 2.5e O 76 %

O 2.6e

O (OC) Co 6 2 Bn 3 benzyl 2.5f O 78 %

O 2.6f

88 O (OC) Co 6 2 TIPS 4 TIPS 2.5g(crude) O 69 % from

O 2.6g 2.4g

Table 2.7: The complexation results of various a-substitutions substrates enynones.

With a series of the vinylogous Nazarov cyclization reaction precursors with different a- substituent groups in hand, attention was turned to the transformation of the cycloheptyne-Co2(CO)6 complexes via the thermally induced vinylogous Nazarov cyclization reaction. Accordingly, complexes 2.6d-g were submitted to the previously

o optimized conditions: three equivalents of SnCl4 in dichloromethane at 0 C to RT. The cyclization results are listed in Table 2.8.

89 O Co2(CO)6 (OC)6Co2 R O O 3 equiv. SnCl4 O

CH Cl , T, t 2 2 O R O 2.6d-g 2.7d-g

Entry R Starting Time (t)/ Product Product/

Material Temperature(T) Yield

Co2(CO)6 O o 1 iPr 2.6d 4 h/0 C O 2.7d/ 86 %

Co2(CO)6 O o 2 ethyl 2.6e 12h/ 0 C to RT O 2.7e/ 75 %

Co2(CO)6 O o 3 benzyl 2.6f 20 h/0 C to RT O 2.7f/ 73 %

Bn O

Co2(CO)6 O o 4 TIPS 2.5d 30 min/0 C O 2.7g/ 89 %

TIPS O

Table 2.8: Cyclization reaction results of various a-substituted enynones using SnCl4 as a Lewis acid.

90 The vinylogous Nazarov reactions were all successful, and showed distinct effects from the different R groups at the a- carbon to the ketone. Isopropyl-substituted (-iPr) 2.6d afforded the desired product 2.7d in an excellent yield of 86 % in 4 h (entry 1). Ethyl- 2.6e and benzyl-substituted 2.6f gave the corresponding products 2.7e and 2.7f in good yields, but the reaction took a longer time (75 %, 12 h) and (73 %, 20 h), respectively. Among the most interesting results (entry 4) was triisopropylsilyl-substituted (TIPS) case. The presence of such a bulky group at a- position allowed a rapid cyclization (30 minutes reaction time at 0 oC) and the intended product 2.7g was isolated in an excellent yield of

89 % under the analogous reaction conditions for the other cases. When comparing all cyclization resultants, it is evident that the cyclization is preferred for the larger (bulky) groups at the a-site. It was realized that the reaction times correlated with the size of the attached a- groups in the following order: TIPS > iPr > benzyl » ethyl > methyl. The statement of steric bulk is evidenced using conformational A values. As reported by Eliel et al.173 the A values are 1.70, 1.75, 1.76, and 2.15 kcal/mol of Me-, Et-, Bn-, and iPr- groups, respectively. The one of TIPS is not reported but is expected to be greater than the

A value of TMS- group (2.5). This trend can be explained using predominantly steric effects. Since the methyl group (2.6b) was the smallest a-substituent, it may lack the steric bulk that is necessary to enforce the requisite s-trans/s-trans confirmation of the Nazarov backbone precursors, which may allow a reasonable population of an unproductive s-cis conformer. Conversely, the TIPS group may enforce a near 100 % population of these s- trans-conformers. In terms of electronic factors, there may be a small contribution on the

TIPS-substituted case (2.6g). Since trialkylsilyl groups are slightly less inductively donating than alkyl groups, the partial positive charge at b- carbon (the most electrophilic

91 site, E+) would increase slightly on the formed intermediate cationic Lewis acid complex, accelerating the overall reaction of the TIPS substituted case (30 minutes). The suggested trend is summarized in Figure 2.2.

Co2(CO)6 less favourable O slower O o lower yield 2.7b (56 %, 24 h, 0 C to RT)

O Me

Co2(CO)6 Co2(CO)6 O O O O

Et O O Bn

2.7f (73 %, 20 h, 0 oC to RT) 2.7e (75 %, 12 h, 0 oC to RT)

Co2(CO)6 O O 2.7d (86 %, 4 h, 0 oC)

O iPr

Co2(CO)6 more favourable O faster O 2.7g (89 %, 30 min, 0 oC) higher yield O TIPS

Figure 2.2: Trend of the reactivity of different a-substitutions toward the cyclization.

Overall, the impact of a variety of R groups at the a- site we surveyed. It is mostly based on their size, on the facility of the cyclization reaction, and the efficiency of the

92 produced products, and the geometry of the substrate. It was found that the bulky (a-TIPS) substitution cyclized most readily with highest yield, suggesting that this substituent has a good combination of the most preferred formation of the requisite s-trans/s-trans confirmation and perhaps a beneficial electronic effect.

2.2.3 VINYLOGOUS NAZAROV CYCLIZATION REACTION: b-

SUBSTITUTED CASE

The impact of substituents at the ketone a- position on the productivity of the vinylogous Nazarov cyclization is clear, with TIPS and iPr groups being the most beneficial. The effect of b-substitutions on the efficiency of the vinylogous Nazarov cyclization was studied subsequently.

To obtain the relevant precursor for a b-substituted case, a synthetic route which is similar to the one explored earlier was used. Scheme 2.9 illustrates the overall synthesis of the complexed precursor 2.6h. A b-methyl group was chosen for this investigation due to it being the simplest change, as well as taking advantage of the commercial availability of the aldehyde precursor (tiglic aldehyde).

93 H OH O O 1) PDC, CH Cl , RT, 12 h 1) nBuLi, THF, -78 oC 2 2 2) Co (CO) , CH Cl , O 2) Tiglic aldehyde, 2 8 2 2 0 oC, 2 h -78 oC to 0 oC O 2.3b 2.4h (87 %)

O O (OC)6Co2 (OC)6Co2 (OC)6Co2 O O O O

O O O obtained: 2.6h' (18 %) 2.6h (E-, 48 %) expected: 2.6h (Z-, 18 %)

Scheme 2.9: Synthetic route toward the formation of the complexed cross-conjugated dienynone for b-substituted case.

The preparation of the vinylogous Nazarov precursor was initiated by the reaction between the terminal alkyne (2.3b) and nBuLi at -78 oC, following by the addition of 2 equivalents of the tiglic aldehyde ((E)-2-methylbut-2-enal). After 12 h stirring, the work- up and purification procedures, afforded 87 % yield of the corresponding alcohol 2.4h. The presence of the b-methyl group was confirmed by the appearance of the doublet at 1.67 ppm in 1H NMR spectrum, in addition to the chemical shift of 12.2 ppm in the13C NMR spectrum.

The resultant alcohol then underwent the oxidation reaction under the standard reaction conditions of (1.5 equivalents PDC in CH2Cl2 at room temperature). The resulting product was not purified, and was used as a crude material in the following reaction step.

Complexation reaction using an excess Co2(CO)8 in CH2Cl2 proceeded successfully in 2 h.

Upon completion, two separable isomers were obtained originally assumed to E-2.6h and

94 Z-2.6h, in 48 % and 18 % yields, respectively. The major product has been found to be the

E- isomer configuration. NOESY 2D-NMR spectrum was obtained for the E- 2.6h isomer.

A strong through-space correlation was detected between the a- methyl protons and the b- methyl protons at 1.77 and 1.95 ppm. For confirmation of this isomer stabilities, density functional theory calculations (DFT, B88-PWI functional, dzvp basis set) were performed on both isomers (E-2.6h) and (Z-2.6h) (see Appendix). Geometries of both isomers are depicted in Figure 2.3. Based on the data obtained, the E- isomer was found to be more stable than the Z- isomer. Ultimately, the structure of the purported Z-2.6h had to be reassigned. Due to the exceptionally downfield shift 7.7 ppm of the vinylic proton in the

1H NMR spectrum of this compound, and its small coupling constant to the methyl group

(J = 1.2 Hz), we are assigning the minor product of the isomerized ketone (2.6h¢, Scheme

2.9).

E-isomer (2.6h) Energy = -4252.57372 au

Z-isomer (2.6h) Energy = -4252.56027 au

Figure 2.3: Optimized geometries of (E-2.6h) and (Z-2.6h) isomers (blue = Co, red = O, gray = C, white = H).

95 With the precursors complex E- 2.6h in hand, the vinylogous Nazarov reaction was

o attempted under the standard reaction conditions (3 equivalents SnCl4 in CH2Cl2 at 0 C to

RT). The progress of the reaction was monitored by TLC, and after leaving it for 24 and

48 hours, it was noticed that the starting material spot was unchanged. The reaction was allowed to stirr longer at room temperature. After 7 days, it was noticed that new spots has emerged, one coloured and one UV active. It was suspected that (E-2.6h) was converting to the cyclization product, and the other spot might be the decomplexed starting material.

This assumption was proven to be correct through 1H NMR spectroscopy for both products, showing the successful conversion of E-2.6h to the desired product 2.7h in very low yield

(12 %, 33 % brsm). The majority of material was found to be the reformed E- isomer of

2.5h, the decomplexed starting material in 17 % yield (Scheme 2.10). The regioisomer E-

2.5h was examined using NOESY 2D-NMR spectrum. Although a much weaker correlation was detected between the vinyl proton and a- methyl group, a strong correlation was found between the a- methyl group (1.86 ppm) and the protons of the b-methyl group

(1.98 ppm), supporting 2.5h as the E- isomer.

O O Co2(CO)6 (OC)6Co2 O O O 3 equiv. SnCl4 O

CH Cl , 0 oC, 7 days 2 2 O O O E-2.6h 2.7h (12 %) E-2.5h (17 %) (33 % brsm)

Scheme 2.10: Vinylogous Nazarov cyclization of b-methyl via SnCl4 as a Lewis acid.

96 It is evident that the presence of b-alkyl group has reduced the efficiency of the vinylogous Nazarov cyclization reaction. The introduction of modestly bulky group clearly slowed the ring closure step, due to the impact of the steric hindrance on electrophilicity.

Thus, reaction required 7 days (compared to 24 h for 2.6b), proceeded with a low yield (12

%) of cyclization product 2.7h, thus creating the opportunity for competitive decomplexation to occur.

The resultant complex 2.7h has been fully characterized by 1H/13C NMR, IR, and

MS spectroscopies. The relative configuration of the two protons (Ha and Hb) located on

3 a b the cycloheptyne-Co2(CO)6 unit was assigned using the J coupling constant (H ,H ). The magnitude of 3J was found to be 1.6 Hz (Figure 2.4), indicating a cis- configuration between the two protons, and consistent with the expected dihedral angle (q = 82.660).

Co2(CO)6 O O Hb O Ha

2.7h (cis-)

3 a b J (H -H ) = 1.6 Hz

3 Figure 2.4: Calculated coupling constant J for the cycloheptyne-Co2(CO)6 with b-methyl substitution.

97 2.2.4 VINYLOGOUS NAZAROV CYCLIZATION REACTION:

INDOLE SYSTEM

In order to expand the scope of the vinylogous Nazarov cyclization, different substrates with nucleophilic portion other than benzenoid ones were desired. Therefore, a system containing N-methyl indole, a p-excessive heterocyclic ring system, was selected as an alternative, due to the high nucleophilic reactivity of that heterocycle. It has been found that indoles derivatives react more rapidly with electrophiles than most benzenes,174-

182 as reflected in its Mayr N value of 5.75.183a

The synthetic pathway toward the formation of the vinylogous Nazarov cyclization precursor of the hetero-fused indole system is depicted in Scheme 2.11. The route started with the Sonogashira cross-coupling reaction of commercially available 2-iodo-1-methyl indole (2.10) and TMS-acetylene (2.11) that synthesized according to literature,183b including fluoride-mediated desilyation to furnish the reaction acetylide, which gave corresponding alcohol 2.12 in excellent yield (87 %).

98 OH Pd(PPh3)4 3 mol% I CuI 5 mol% N N OH TMS + - Bu4N F , THF, Et3N 2.10 2.11 RT 2.12 (87 %)

PDC, CH2Cl2 Co2(CO)8

N O o N O RT CH2Cl2, 0 C Co2(CO)6 2.13 (60 %) 2.14 (94 %)

Scheme 2.11: Synthesis of the vinylogous Nazaro cyclization precursor of indole system.

This enynol (2.12) was treated with PDC for the oxidation reaction. Using this protocol, the alcohol successfully converted to the corresponding ketone 2.13 in 60 % yield. At this point the alkyne function of the enynone was subjected to the complexation with an excess of Co2(CO)8, generating the corresponding hexacarbonyldicobalt complex

2.14 in an excellent yield (94 %). Interestingly, this complex was obtained as a dark green compound (most cobalt complexes are red-(brown) in colour). Thus, UV-vis spectra were obtained for both complexes 2.6a (anisole system) and 2.14 (indole system), and differeces are shown in Figure 2.5. A red shift of 53 nm was observed for the highest wavelength absorption of cobalt complex 2.14 in comparison to the complex 2.6a, presumably due to the highly conjugated system of this precursor (2.14) along with the bicyclic structure of the indole moiety giving a higher HOMO. Therefore, the energy required for the electronic transition is less, resulting in higher lmax of indole system (lmax = 598 nm, red shift). The complex was quite air stable and easily purified by column chromatography.

-1 -1 Figure 2.5: UV-vis spectra of anisole system (2.6a, red, lmax = 545 nm, e = 221 M cm )

-1 -1 and indole system (2.14, green, lmax = 598 nm, e = 1199 M cm ).

With cobalt complex (2.14) in hand, the stage was set to attempt the vinylogous

Nazarov cyclization. Once again, the now-standard conditions with SnCl4 were employed for this vinylogous Nazarov reaction. The cyclization proceeded successfully to generate the desired cycloheptyne-Co2(CO)6 2.15 in 65 % yield (Scheme 2.12).

O 3 equiv SnCl4

N O CH Cl , 0 oC to RT, 48 h 2 2 Co2(CO)6 Co2(CO)6 N

2.14 2.15 (65 %)

Scheme 2.12: Cyclization result of indole-based system.

100 2.2.5 VINYLOGOUS NAZAROV CYCLIZATION REACTION: NON-

AROMATIC SYSTEM

Upon the establishment of the applicability of the vinylogous Nazarov on a heteroaryl system, it is important to expand this chemistry further, through using different, non-aromatic nucleophilic groups. The DFT calculation of alkenes C and D were obtained at the B88-PW91/dzvp level of theory (Scigress Explorer, CAChe, see Appendix). Both the activation energies (DG‡) and free energies of cyclization (DG) suggested that the vinylogous Nazarov cyclization would be accessible. The values presented in Scheme 2.13 are in approximate correlation with the recently reported DFT results for the Nazarov electrocyclization of oxy- and halo-pentadienyl cation intermediates.184a

H Co (CO) O 2 6 (OC)6Co2

OH DG = -2.5a DG‡ = 15.4a C C'

H Co (CO) O 2 6 (OC)6Co2

OH DG = -6.0a DG‡ = 11.6a D D'

Scheme 2.13: DFT results for the vinylogous Nazarov cyclization reactions of enyne group cationic intermediates at the B88-PW91/DZVP level. a (kcal/mol).

101 Thus, several different precursors with non-aromatic systems were attempted with the intent of obtaining the vinylogous Nazarov products (Figure 2.6). Interestingly, none of them were converted successfully to intended products. In the case of precursor 2.16, the pyran ring was opened instead of the cyclization reaction, indicating that the enol ether of the dihydro-pyran was too sensitive. Styrene system 2.17 gave only decomplexed starting material back. Allyl-TMS 2.18 and precursor 2.19 gave no reaction.

O O O O (OC)6Co2 (OC)6Co2 (OC)6Co2 (OC)6Co2

O Ph tBu

TMS 2.16 2.17 2.18 2.19

Figure 2.6: A series of non-aromatic precursors.

After these failures, cyclohexene substrates were targeted. As summarized in

Scheme 2.14, the substrate preparations started with 1-ethynyl-1-cyclohexane (2.20), which, with 1.5 equivalents nBuLi in THF at -78 oC and methacrolein (a-methyl) or 2-

(triisopropylsilyl)acrylaldehyde (a-TIPS), afforded alcohol 2.21a in 49 % yield and 2.21b in 40 % yield.

102 OH R 1) 1.5 equiv. nBuLi, THF, -78 oC

O o 2) methacrolein or TIPS , 0 C

2.20 2.21a (R = CH3), 49 % 2.21b (R = TIPS), 40 %

O O (OC) Co R 6 2 R Co (CO) , CH Cl PDC, CH2Cl2 2 8 2 2

12 h, RT 2 h, 0 oC

2.22a (R = CH3), 71 % 2.23a (R = CH3), 80 % 2.22b (R = TIPS), crude 2.23b (R = TIPS), 60 % for 2 steps

Scheme 2.14: Non-aromatic precursors formation toward the vinylogous Nazarov cyclization.

Both alcohols underwent oxidation reaction with PDC. Unfortunately, the resultant ketone 2.22b was not easily purified; however, the conjugated ketone 2.22a formed in good yield (71 %). Thus, to the crude product of 2.22b and the pure 2.22a an excess amount of

o Co2(CO)8 was added under the standard conditions (CH2Cl2, 0 C to RT, N2, 2 h), followed by purification. Compounds 2.23a and 2.23b were isolated as dark red materials in 80 % and 60 % (2 steps) yields, respectively.

With 2.23a and 2.23b available, these complexed compounds were subjected to the vinylogous Nazarov cyclization under the appropriate reaction conditions (3 equivalents

o SnCl4, CH2Cl2, 0 C, N2). For the complex 2.23a, having a-methyl substitution, two regioisomers were formed 2.24a and 2.24a′ in a total yield of 44 % after 12 h reaction time.

On the other hand, the 2.23b (a-TIPS) complex, cyclization efficiency was enhanced and

103 essentially one isomer was formed in 62 % (80 % brsm), after only 4 h. Table 2.9 summarizes the cyclization results for the nonaromatic system.

O (OC) Co Co2(CO)6 Co2(CO)6 6 2 R 3 equiv. SnCl4, A O B O CH2Cl2, t, T R R

2.23a (R = CH3) 2.24a (R = CH3) 2.24a' (R = CH3) 2.23b (R = TIPS) 2.24b (R = TIPS) 2.24b' (R = TIPS)

Entry R Starting Time Temperature Ratio A:B/

Material (t) (T) Yield

1 Me 2.23a 12 h 0 oC to RT 2:1/44 %

2 TIPS 2.23b 4 h 0 oC >30:1/ 62 %

80 % (brsm)

Table 2.9: Formation of two isomers via cyclization reaction of the non-aromatic system.

The effect of the bulky a-TIPS group can again be observed. Reaction of 2.23b occurred at 0 oC, while in 2.23a the reaction required room temperature. The small amount of starting material recovered in the case of 2.23b stems in part from the identical TLC elution characteristics of 2.23b and 2.24b, making it difficult to tell when complete starting material consumption had occurred.

104 The matter of the double bond regioisomer mixture is difficult to pin down exactly.

As a propargyldicobalt cation is generated immediately following ring closure, one would normally expect the more substituted alkene to predominate, in keeping with the Zaitsev orientation of E1 elimination reactions.184b Conversely, the conditions are likely to generate a small amount of acid, which are also capable of causing alkene isomerization, again predominantly towards the more substituted isomer. It is therefore possible that the more substituted : less substituted alkene isomer ratios to be different in shorter/lower temperature reaction conditions (as in 2.24b) and longer/higher temperature conditions (as in 2.24a), while expecting predominant tetrasubstituted alkene formation in both cases.

These may loosely be called kinetic and thermodynamic conditions, respectively (Figure

2.7).

L.A. O Co (CO) (OC) Co Co (CO) 2 6 6 2 R H 2 6 kinetic A O O path A L.A. R H R more substituted alkene 2.23a (R = CH3) 2.23b (R = TIPS) path B H+ Base

Co2(CO)6 Co (CO) H 2 6 H Co2(CO)6 isomerization thermodynamic B O A O O path B L.A. R R H R Base

path A

Figure 2.7: Alkene isomerization during cyclization reaction.

105 2.3 PROPOSED CYCLIZATION REACTION MECHANISM

To promote the ring-closure step, it was necessary to use an appropriate Lewis acid to facilitate the reaction. Most of our previous group’s work had relied on using BF3•OEt2 as the preferred Lewis acid, yet SnCl4 has proven to act as more effective Lewis acid than the BF3•OEt2 for the cyclization reaction of this research. Again, several studies have

185,186 shown improved reaction efficiency when switching from BF3•OEt2 to SnCl4. To our delight, the cyclization reaction progressed easily in the presence of 3 equivalents SnCl4.

Scheme 2.15 illustrates the proposed reaction mechanism, which qualifies as a seven- membered ring process that could be described as intramolecular electrocyclization. The initial step was the complexation of SnCl4 to the oxygen on carbonyl group. The activation of the carbon atom was caused by the Lewis acid coordination, that leads to increase the electrophilicity, forming a formal heptatrienyl cation 2.25. Subsequently, the terminal electrophilic carbon was attacked by the reactive nucleophile (i.e. enyne or aryl group), generating very stable intermediate propargylic carbocation 2.26, positive charge delocalized onto the alkyne-Co2(CO)6 moiety. After that, elimination step occurred by deprotonation of the carbon atom (a- to the positive charge), and protonation of the enolate forms the desired cycloheptyne-Co2(CO)6 2.27.

106 L.A. L.A. O O (OC)6Co2 (OC) Co O R3 6 2 (OC)6Co2 R3 R3 R1 L.A. R1 R1

R2 R2 R 2.25 2

Co2(CO)6 Co2(CO)6 R R 1 - H+, + H+ 1 O O R R L.A. 2 2 H H R3 R3 2.27 2.26

Scheme 2.15: Proposed reaction mechanism of the vinylogous Nazarov cyclization reaction.

The reaction also may be regarded as an electrophile/nucleophile combination reaction. Due to donation of electron density to the alkene by having conjugation with the cobalt coordinated enyne (blue coloured site), such alkenes have N (nucleophilicity) values

(see Table 2.10) of -1 according to Mayr’s scale.72,187 By comparison, the electrophilicity of unsaturated ketone Lewis acid complex is unknown, but it is likely to be close to the benzaldehyde-BCl3 complex (red coloured site). In this case the Mayr E value is +1 (Figure

2.8).71 Since this combination give an N+E ³ -3 value according to Mayr’s scale, a reaction is quite possible.

107 L.A. O (OC)6Co2 R3 R1 E+ site

BCl3 - most Nu site O

(OC)6Co2 R E = +1

N = -1 (R = TMS)

Figure 2.8: Reported N and E values according to Mayr’s scale.

Molecule N value

(OC) Co 6 2 TMS -1.11164

(OC) Co 6 2 TMS Ph 1.3371

(OC) Co 6 2 H -0.44164

Table 2.10: N values of various enyne groups. `

108 2.4 REDUCTIVE DECOMPLEXATION OF CYCLOHEPTYNONE-

Co2(CO)6 COMPLEXES

After the successful formation of cycloheptynone-Co2(CO)6 complexes via vinylogous Nazarov reactions, it was important to seek further extension of this chemistry to provide an access to a metal-free seven-membered ring system. Availability of solely organic material would make it an easy starting point for the synthesis of for example natural products. Removal of cobalt moiety in the case of 2.7d was effectively achieved by the reductive decomplexation using triethylsilane in the presence of bis(trimethylsilyl)acetylene (BTMSA) (Scheme 2.16) using conditions developed by

Djurdjevic and Green.92

Co2(CO)6 SiEt3 O O o O O Et3SiH (5 equiv), DCE, 65 C

O O Me3Si SiMe3 (2 equiv) 2.7d 2.28 (87 %)

Scheme 2.16: Reductive decomplexation via hydrosilation conditions.

The reductive decomplexation reaction of compound 2.7d was examined by heating in degassed dichloroethene (DCE) at 65 oC with 5 equivalents of triethylsilane and

2 equivalents of bis(trimethylsilyl)acetylene (BTMSA), affording the corresponding vinylsilane 2.28 by the removal of Co2(CO)6 unit. This was a straightforward and highly regioselective hydrosilation reaction ( a- to the EWG, carbonyl group) in high yield (87

109 %). The high regioselectivity was likely due to the preference that the bulky silyl group remain away from the more sterically bulky substituent, as well as being a- to the ketone.

The formation of vinylsilane 2.28 was evident from IR spectroscopy, which showed the disappearance of cobalt complex CO stretches at 2096, 2057, and 2017 cm-1, and appearance of a strong absorption at 1641 cm-1 (indicating the presence of the conjugated carbonyl group of ketone). In addition, the presence of the triethylsilyl group was confirmed by observing 9 protons at d 0.81 and 6 protons at d 0.95 in the 1H NMR spectrum. The regioselectivity of the reaction giving product (2.28) was confirmed via the

NOESY 2D-NMR spectrum (Figure 2.9). The NOESY showed correlation between the vinyl proton b- to the carbonyl group and the proton (Ha) in the aromatic ring. Furthermore,

NOESY demonstrated the correlation between triethylsilyl protons and vinyl proton (b- to the carbonyl group) only, but not with aromatic proton (Ha) (refer to Experimental Section for details).

δ 6.43 δ 7.07

Ha H SiEt3 O O

Figure 2.9: NOESY correlations observed in 2.28.

110 The next reaction step was protodesilylation with trifluoracetic acid (TFA) as a good proton source. The reaction was stirred at room temperature for 24 h and only 10 % conversion was observed. Warming up the reaction at 40 oC for 4 h, afforded the alkene

2.29 in 40 % (66 % brsm) (Scheme 2.17). The isolation of final reductive product (2.29) was most evident in the 1H NMR spectrum, which showed the disappearance of the 9 and

6 proton resonances at d 0.81 and d 0.95, respectively, as well as raise of two vinyl protons at d 6.95 and d 6.11, with a ca. 12 Hz coupling.

SiEt3 O O O O TFA, DCE, 4 h

O O

2.28 2.29 (40 %)

Scheme 2.17: Protodesilylation using trifluroacetic acid.

In summary, reductive decomplexation was successfully achieved using a hydrosilylation/protodesilylation protocol adopted from literature, 92,105,107 in two reaction steps.

111 CHAPTER 3 CONCLUSIONS AND FUTURE WORK

3.1 CONCLUSION

In this research, we investigated the preliminary formation of cycloheptyne-

Co2(CO)6 complexes via vinylogous Nazarov cyclization reactions, under thermal condition. This dissertation has been mainly focused on designing the precursors of vinylogous Nazarov cyclization reactions, and then enabling the cyclization using Lewis acid, in order to find the best precursors and conditions for better cyclization efficiency.

The required ketones complexed precursors were prepared from commercially available starting materials through six reaction steps. DFT calculations have confirmed the possibility of Nazarov cyclization with these complexed precursors. It was found that

SnCl4 was the appropriate Lewis acid for this cyclization approach. A range of aromatic nucleophiles starting materials have been examined such as: 1) carbocyclic arenes including: (3-anisyl (N = -1.18),71 dimethoxy phenyl (N = 2.48),164 and 3,4,5-trimethoxy phenyl (N = unknown); 2) indoles (1-methylindole, N = 5.75).183a Non-aromatic nucleophiles were also investigated. All the listed aromatic nucleophiles and cyclohexen-

1-yl, were found to be capable of participating in the formation of the corresponding cycloheptyne- Co2(CO)6 complexes. Substitutions effects have been examined using different a- groups with the dimethoxy arene. From the obtained results, having a bulky group at the a- position to the carbonyl group provided the best cyclization result. TIPS found to be the most appropriate bulky group placed at this position because it is promoting the s-trans/s-trans conformation. On the other hand, b-alkyl substitution slows down the

112 cyclization rate and forms the cyclization product in a very low yield product. Reductive decomplexation was successfully produced the desired alkene in two reaction steps following the known procedures of triethylsilane in the presence of bis(trimethylsilyl)acetylene (BTMSA) followed by desilytion using TFA.

3.2 FUTURE WORK

Many different modifications, tests, and experiments have been left for the future.

Future work concerns deeper studies of reaction mechanisms, new proposals to try different starting materials, Lewis acid, or applying new chemistry to the last products formed. There are some ideas that would be attempted in order to expand this chemistry.

Demonstrating that formation of cycloheptyne-Co2(CO)6 via the vinylogous

Nazarov cyclization would further broaden the range of possibilities of synthesizing seven- membered ring systems. As mentioned above, the enhancement of the reaction rate of the cyclization was achieved with the use of different substitutions at the a- position to the carbonyl group as well as using different starting materials, and Lewis acids. Therefore, it is highly recommended that designing new starting materials would likely result in improved cyclization with electron-withdrawing groups at a- position (i.e. ester).124,168-170

In standard Nazarov reactions, it has been found that ester groups enhance the regioselectivity of the double bond as well as it is ability to bind a Lewis acid in a bidentate fashion, further enhancing the s-trans/s-trans conformation. In addition, Nazarov reactions with electron-withdrawing group at a-site are considered polarized Nazarov reaction through developing positive charge at the most electrophilic carbon of the intermediate

113 cation; therefore it will be interesting to extend the ring size of this approach of Nazarov reactions. Specific vinylogous Nazarov precursor are as shown in Figure 3.1.

O O (OC)6Co2 (OC)6Co2 R2 R X

R1 = EDG R = ester R = ester 2 X = CH2

Figure 3.1: Electron-withdrawing group a-site to carbonyl.

The possibility of the one-pot Nicholas-Nazarov reactions through nucleophilic trapping the stable propargylic carbocation-electrocyclization intermediate would be interesting. One-pot reactions have not been reported so far. Scheme 3.1 illustrates the idea of this combination. It may be challenging to find appropriate nucleophiles that trapped the propargylic carbocation. Allyl-TMS is a suitable nucleophile with N value of 1.68 that according to Mayr’s scale able to react with propargylic carbocation.

114 Nu-

Co2(CO)6 Nu Co2(CO)6 Nicholas reaction O O

H TIPS H TIPS H

- SiMe Nu = 3

Scheme 3.1: One-pot Nicholas-Nazarov reactions.

Another long-term goal of this approach to the Nazarov cyclization is to determine the mechanistic properties of the ring closure step. It is widely established, theoretically and experimentally, that a typical Nazarov cyclization of a cross-conjugated dienone occurs under conrotatory ring closure, as explained in Chapter 1. Furthermore, it has been reported that a photochemical induction of this reaction may induce disrotatory ring closure. It is worth mentioned that the diasteroselectivity of this approach (6 p system) under thermal conditions is still unknown (Figure 3.2a). For purpose closer to that of this work, the cyclization of a model heptatrienyl cation intermediate, it is evident through theoretical analysis that orbital symmetry for conrotatory ring closure is forbidden (Figure

3.2b). Thus, we proposed that disrotatory ring closure would be possible (Figure 3.2c).

This issue may be addressed by the introduction of other nonaromatic nucleophiles, that might allow the investigation of stereospecifity of the cyclization product.

115 a) L.A. O O H+ or Lewis acid unknown disrotatory in principle

b) L.A. L.A. O O O + H or conrotatory

Lewis acid

HOMO

c) L.A. L.A. O O O + H or disrotatory

Lewis acid

HOMO

Figure 3.2: HOMO orbitals of a heptatrienyl cation.

After the investigation of a series using a variety of functional groups on the a- sites of the dienyneone moieties and the only example of the b-site (Me) group, and a range of different nucleophilic groups, we are in the position to design the vinylogous Nazarov precursor that would definitely determine the direction of the cyclization reaction, Scheme

3.2 presentes the suggested precursor for this chemistry, but the reaction will require nucleophilic trapping of the cyclization to preserve the stereochemistry about the newly formed bond. In principle and under a thermal condition 6 p system might be a disrotatory ring closure.

116 L.A. L.A. O O O (OC)6Co2 (OC) Co R (OC)6Co2 6 2 1 R1 R1 L.A. X X X R 2 R2 R2

R1 = TIPS R2 = Me HOMO X = CH2

disrotatory in principle

Co (CO) Co (CO) Nu 2 6 2 6 X Nu- X SiMe Nu- = 3 H O H O tautomerization L.A. H H R R1 R 1 R2 2

Scheme 3.2: Orbital symmetry of the heptatrienyl cation intermediate.

To the best of our knowledge, the acid-promoted cyclization of linearly conjugated metal mediated p-extended carbonyls (known as iso-Nazarov) is limited. Seeing the ready ability to synthesize cycloheptyne-Co2(CO)6, further extending the chemistry of iso-

Nazarov reactions to form a seven-membered ring version is reasonable (Scheme 3.3). On the basis of our previous findings, the coordination of a Lewis acid to the carbonyl would ultimately give a highly stable intermediate propargylic carbocation upon cyclization, thus we predict the formation of seven-membered ring version of the iso-Nazarov could be possible. The cationic rearrangement of the iso-Nazarov may be quite different here.

117 H HO O O R R Lewis acid or H+ R H H

Co (CO) (OC) Co 2 6 (OC)6Co2 6 2

HO R

Co2(CO)6

Scheme 3.3: Designed precursors of the iso-Nazarov approach to form a seven-membered ring.

Further experiments could be done on the synthesized cycloheptyne-Co2(CO)6 complexes rather than reductive decomplexation. As already mentioned in Chapter 1, acetylene-dicobalt hexacarbonyl is used in Pauson-Khand reactions to form cyclopentanones,22-24 it might be then potential to introduce a 5-membered ring system to the prepared cycloheptyne. The suggested structure is presented in Scheme 3.4, ending up with a polycyclic compound that could be a useful entrance to some natural product.

H O Co2(CO)6 H Pauson-Khand R1 O R1 O

R2 R2

R1 = EDG R2 = bulky, EWG

Scheme 3.4: Pauson-Khand reaction of the synthesized cycloheptyne-Co2(CO)6.

118 CHAPTER 4 EXPERIMENTAL SECTION

4.1 GENERAL METHODS AND MATERIALS

Unless stated otherwise, all reactions and manipulations were carried out under a

o nitrogen atmosphere N2. All glassware was dried overnight on an oven (110 C), and cooled in a desiccator. All glassware and their reagent contents prior to any reactions were placed under 0.1 Torr vacuum. Solvents used for reactions were obtained from a solvent purification system (Innovative Technologies) and used without further treatment. All reagents were purchased from Sigma-Aldrich, except dicobalt octacarbonyl (Strem

Chemicals Inc.), and tetrabutylammonium fluoride TBAF (Oakwood Chemicals).

Tetrakis(triphenylphosphine) palladium(0) was prepared from palladium dichloride according to method published by Heck.188 All commercial chemicals were used without further purification. Transferring of liquid reagents as well as solvents were done via oven- dried syringe and under positive nitrogen pressure. An acetone/dry ice bath was used for the reactions that carried out at -78 oC; and a water/ice bath was used for those carried out at 0 oC. The progress of reactions was monitored using aluminum-backed TLC strips

(thickness: 250 µm, indicator: F-254) purchased from SiliCycle Inc. Silica gel (SiliaFlashâ

P60, particle size: 40-63 µm, mesh: 230-400) was used for purification techniques of flash chromatography. Glass-backed TLC plates (thickness: 1000 µm, indicator: F-254) was used for preparative TLC purification techniques. Both materials were purchased from

SiliCycle Inc. Radial chromatography was carried out on silica gel plates (thickness: 2000

µm, indicator: F-254) made in house.

119 1-Ethynyl-3-methoxybenzene, 1-ethynyl-3,5-dimethoxybenzene and 5-ethynyl-

1,2,3-trimethoxybenzene are commercially available; however they have been prepared by two step reactions according to literature procedures the first step is a Sonogashira cross- coupling reaction using halogenated aromatic reagent with trimethylacetylene

(TMSA),157,158 and second step is a desilyation reaction with tetrabutylammonium fluoride

(TBAF).159

4.2 INSTRUMENTATION

1H (and 13C) NMR spectra were carried out in deuterated chloroform solvent and were recorded on 300 MHz and/or 500 MHz Bruker Avance spectrometer (at 75 MHz and

125 MHz) for 1H and 13C, respectively at room temperature. The NMR samples were prepared by dissolving about 20 mg of material in 1 mL of deuterated solvent, and in some cases filtration over a Celia plug was necessary. For both 1H-NMR and 13C-NMR spectra, chemical shifts are reported in parts per million (ppm) using 7.27 ppm of the residual

1 13 CHCl3 ( H) and 77.1 ppm for CDCl3 ( C) as the reference. Coupling constants were reported in Hertz (Hz). Infrared (IR) spectroscopy was obtained from a Bruker alpha FT-

IR spectrometer performed in Prof. Rawson’s lab (University of Windsor). The spectra peaks were reported in wavenumber (cm-1). UV-VIS spectroscopy was performed on a

Varian UV/Visible Cary 50 spectrophotometer. High-Resolution Mass Spectroscopy

(HRMS) results were obtained by two instruments: 1) direct liquid injection for

Electrospray Ionization (ESI) or direct contact sampling using the Atmospheric Solids

Analysis Probe (ASAP), on a Waters XEVO G2-XS Time-of-flight (TOF) spectrometer performed at the University of Windsor; 2) by means of a Direct Insertion Probe-Electron

120 Ionization method (70 eV), on a Waters/Micromass GCT (GC-EI-CI Time of Flight Mass

Spectrometer) performed at the McMaster Regional Center for Mass Spectrometry.

Melting points were measured with a Thomas Hoover, Uni-MeltÓ capillary point apparatus.

DFT calculations were run using “B88-PW91 functional using a basis set” (CAChe/

Scigress Explorer).

4.3 EXPERIMENTAL DATA

Synthesis of 5-(3-methoxyphenyl)-2-methylpent-1-en-4-yn-3-ol (2.4a):

General procedure A: In a round bottom flask, 1-ethynyl-3-methoxybenzene

(2.3a) (0.120 g, 0.904 mmol) was dissolved in dry THF (5 mL). The flask was cooled to -

o n 78 C under N2, at which point BuLi (2.5 M in hexanes, 0.16 mL, 1.4 mmol, 1.5 equiv) was added dropwise at -78 oC and allowed to stir. After 45 minutes, the reaction mixture was allowed to warm to 0 oC. At this point was added a solution of methacrolein (2 equiv,

0.13 g, 0.15 mL, 1.8 mmol) dissolved in THF (3 mL) and allowed to stir for 30 minutes.

After this time, the reaction mixture was allowed to warm to room temperature and then

NH4Cl (aq., sat.) was added. This was extracted with Et2O (3 x 100 mL), then dried with

MgSO4, filtered, and the solvent removed under reduced pressure. The crude material was obtained and purified upon radial chromatography (1:1 hexanes : Et2O) to yield the product

2.4a, as a yellow viscous oil (0.1827 g, 0.904 mmol, 50 % yield); IR nmax 3388 (broad),

121 -1 1 3075, 2943, 2837, 2225, 1702, 1655, 1598, 1576 cm ; H NMR (CDCl3) d 7.19 (apparent t, J=8.1, 1H), 7.05 (apparent t, J=7.8, 1H), 6.97 (m, 1H), 6.88 (ddd, J=8.4, 2.7, 0.9, 1H),

5.25 (s, 1H), 5.02 (s, 1H), 4.98 (d, J=0.9, 1H), 3.81 (d, J=2.4, 1H), 3.79 (s, 3H), 1.93 (s,

13 3H); C NMR (CDCl3) 159.4, 144.1, 129.5, 124.4, 123.7, 116.7, 115.3, 112.7, 87.9, 86.0,

+ + 66.9, 55.4, 18.3; HRMS m/e for C13H14O2 [M -H ] calculated 201.0916, found 201.0915.

Synthesis of 5-(3-methoxyphenyl)-2-methylpent-1-en-4-yn-3-one (2.5a):

General procedure B: In a round bottom flask, alkynol 2.4a (0.0500 g, 0.247 mmol) was dissolved in anhydrous CH2Cl2 (10 mL). To this flask, pyridinium dichromate

(PDC) powder (1.5 equiv, 0.1391 g, 0.370 mmol) was added in one portion, and the mixture allowed to stir at room temperature. Following stirring for overnight, the solution was filtered through a silica gel plug to remove the excess solid. The filtrate was concentrated under reduced pressure and purified by column chromatography (15:1 hexane : Et2O) to obtain the dienynone, 2.5a (0.0426 g, 0.212 mmol, 86 % yield), as a yellow oil;

General procedure C: To a solution of 2.4a (0.2301 g, 1.138 mmol) in anhydrous

CH2Cl2 (10 mL) was added N-methylmorpholine N-oxide (NMO) (3 equiv, 0.3991 g, 3.407 mmol). After stirring the solution for 5 minutes at room temperature, tetrapropylammonium perruthenate (TPAP) (0.0240 g, 0.071 mmol) was added. The reaction mixture was stirred for 12 h, following which it was filtered through Celite and

122 washed with Et2O. Volatiles were removed under reduced pressure and the crude material was then purified by column chromatography (15:1 hexane : Et2O), to afford the product

2.5a as a yellow oil (0.0631 g, 0.315 mmol, 28 % yield); IR nmax 3073, 2926, 2839, 2196,

-1 1 1637, 1598, 1576 cm ; H NMR (CDCl3) d 7.22 (d, J=7.6, 1H), 7.15 (dt, J=7.6, 1.3, 1H),

7.04 (m, 1H), 6.94 (ddd, J=8.3, 4.4, 1.1, 1H), 6.49 (t, J=0.9, 1H), 6.05 (t, J=0.9, 1H), 3.75

13 (s, 3H), 1.90 (d, J=0.4, 3H); C NMR (CDCl3) 180.0, 159.5, 144.9, 130.6, 129.5, 125.4,

+ 121.0, 117.1, 91.0, 85.3, 55.3, 15.7; HRMS m/e for C13H12O2 [M ] calculated 201.0916, found 201.0915.

Synthesis of hexacarbonyl[µ-h4 (5-(3-methoxyphenyl)-2-methylpent-1-en-4-yn-3- one)]dicobalt (Co-Co) (2.6a):

O (OC)6Co2 O

General procedure D: Dienynone 2.5a (0.1551 g, 0.771 mmol) was dissolved in

o anhydrous CH2Cl2 and cooled to 0 C using an ice bath. An excess amount of dicobalt octacarbonyl (Co2(CO)8) was added to this solution and the reaction was stirred while maintaining the temperature at 0 oC. After 2 h, the mixture was concentrated under reduced pressure in a cold water bath, obtaining the crude product as a dark red material. This crude material was purified on a plug of silica, first washing with 100% petroleum ether to remove the remaining Co2(CO)8, followed by a second washing with 100% Et2O to obtain product 2.6a (0.2750 g, 0.639 mmol, 83 % yield), as dark red crystals, m.p. 58-60 oC; UV-

123 -1 -1 vis (CHCl3) lmax = 545 nm, e = 221 M cm ; IR nmax 3081, 2935, 2842, 2093, 2057, 2008,

-1 1 1626 cm ; H NMR (CDCl3) d 7.28 (t, J=7.8, 1H), 7.10 (dt, J=8.1, 0.9, 1H), 7.03 (t, J=2.4,

1H), 6.90 (ddd, J=8.1, 2.4, 0.9, 1H), 5.84 (s, 1H), 5.80 (s, 1H), 3.82 (s, 3H), 2.08 (s, 3H);

13 C NMR (CDCl3) 198.4 (broad), 194.9, 160.0, 144.1, 138.4, 130.3, 126.3, 122.5, 115.5,

+ 114.0, 91.8, 85.8, 55.4, 18.5; HRMS(EI) m/e for C19H12Co2O8 [M -2CO] calculated

429.9297, found 429.9298.

Synthesis of Hexacarbonyl[µ-h4-(2-methoxy-6-methyl-5,6-dihydro-8,9-dehydro-5H- benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7a) para-:

Synthesis of Hexacarbonyl[µ-h4-(1-methoxy-8-methyl-8,9-dihydro-5,6-dehydro-5H- benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7a¢) ortho-:

General procedure E: In a round bottom flask, the complexed dienynone, 2.6a

(0.1120 g, 0.230 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) under N2. Later, a

1.0M solution of tin tetrachloride (SnCl4) in CH2Cl2 (3 equiv, 0.70 mL, 0.70 mmol), was added dropwise to the reaction mixture at 0 oC. The reaction mixture was monitored under

TLC (20:1 petroleum ether : Et2O) and was allowed to warm to room temperature. After complete disappearance of the starting material (24 h). The solution was quenched with

NH4Cl (aq., sat.) and extracted with Et2O (3 x 100 mL), then dried with MgSO4, filtered, and the solvent removed under reduced pressure. A crude mixture isomers para- 2.7a

(major) and ortho- 2.7a¢ (minor). This crude material was purified and separated using column chromatography (20:1 petroleum ether : Et2O) to obtain major and minor products,

124 para- 2,7a (major) (elute first) and ortho- 2.7a¢ (minor) as red maroon crystals. A ratio of

53:24 % yield of the major : minor product was found.

Co2(CO)6 O O

o Para- 2.7a (0.0589 g, 0.121 mmol, 53 % yield), m.p. 68-71 C; IR nmax 2926, 2201,

-1 1 2099, 2062, 2016, 1675, 1606 cm ; H NMR (CDCl3) d 7.25 (s, 1H), 7.09 (d, J=8.4, 1H),

13 6.86 (dd, J=8.5, 2.7, 1H), 3.85 (s, 3H), 2.83 (m, 3H), 1.57 (s, 3H); C NMR (CDCl3) 204.7,

198.1 (broad), 159.5, 136.8, 131.6, 131.4, 118.2, 114.4, 86.9, 78.2, 55.3, 45.9, 38.3, 16.3;

+ HRMS m/e for C19H12Co2O8 [M ] calculated 486.9274, found 486.9260.

Co2(CO)6

o Ortho- 2.7a′ (0.0268 g, 0.055 mmol, 24 % yield), m.p. 64-68 C; IR nmax 2960,

-1 1 2921, 2852, 2098, 2061, 2007, 1677, 1565 cm ; H NMR (CDCl3) d 7.33 (m, 2H), 6.91

(d, J=7.5, 1H), 3.86 (s, 3H), 3.29 (d, J=15.6, 1H), 2.75 (m, 2H), 1.56 (s, 3H); 13C NMR

(CDCl3) 205.2 (broad), 198.2, 156.9, 137.3, 128.4, 127.8, 125.6, 111.3, 91.0, 87.9, 56.0,

+ 45.6, 28.5, 16.4; HRMS m/e for C19H12Co2O8 [M ] calculated 486.9274, found 486.9277.

125 Synthesis of 5-(3,5-dimethoxyphenyl)-2-methylpent-1-en-4-yn-3-ol (2.4b):

Compound 2.4b was prepared according to General Procedure A, using of 1- ethynyl-3,5-dimethoxybenzene 2.3b as starting material (0.2951 g, 1.818 mmol) and methacrolein (2 equiv, 0.2500 g, 0.30 mL, 3.600 mmol). The product was isolated following column chromatography (1:1 petroleum ether : Et2O) as a yellow oil (0.2677 g,

-1 1 1.152 mmol, 64 % yield). IR nmax 3405 (broad), 3083, 2941, 2840, 2225, 1586 cm ; H

NMR (CDCl3) d 6.59 (d, J=2.4, 2H), 6.44 (t, J=2.4, 1H), 5.24 (d, J=0.9, 1H), 5.01 (s, 1H),

13 4.98 (t, J=1.5, 1H), 3.77 (s, 6H), 2.10 ((br s), 1H), 1.93 (s, 3H); C NMR (CDCl3) 160.2,

143.7, 123.4, 112.4, 109.2, 101.7, 87.3, 85.6, 66.4, 55.1, 17.9; HRMS(EI) m/e for

+ C14H16O3 [M ] calculated 232.1099, found 232.1090.

126 Synthesis of 5-(3,5-dimethoxyphenyl)-2-methylpent-1-en-4-yn-3-one (2.5b):

General Procedure F: In a round bottom flask, compound 2.4b (0.0261 g, 0.111 mmol) was dissolved in anhydrous CH2Cl2 (10 mL). To this flask, pyridinium chlorochromate (PCC) powder (1.5 equiv, 0.0361 g, 0.166 mmol) was added in one portion, and allowed to stir at room temperature. Following stirring overnight, the solution was filtered through a silica plug to remove the excess solid. The filtrate was concentrated under reduced pressure and purified upon column chromatography (15:1 hexane : Et2O) to obtain the pure product 2.5b (0.0119 g, 0.052 mmol, 47 % yield), as a yellow oil.

Compound 2.5b was prepared according to General Procedure B, using compound 2.4b as starting material (0.0446 g, 0.191 mmol) with pyridinium dichromate

(PDC) powder (1.5 equiv, 0.1077 g, 0.286 mmol). The product was isolated following column chromatography (15:1 petroleum ether : Et2O) as a yellow oil (0.0381 g, 0.165

-1 1 mmol, 87 % yield). IR nmax 2930, 2842, 2198, 1678, 1636, 1587 cm ; H NMR (CDCl3) d 6.99 (d, J=2.7, 2H), 6.51 (m, 2H), 6.08 (s, 1H), 3.54 (s, 6H), 1.95 (s, 3H); 13C NMR

(CDCl3) 180.3, 160.6, 145.2, 130.7, 121.4, 110.5, 103.9, 91.3, 85.3, 55.5, 16.1; HRMS m/e

+ for C14H14O3 [M ] calculated 231.1021, found 231.1025.

127 Synthesis of hexacarbonyl[µ-h4 (5-(3,5-dimethoxyphenyl)-2-methylpent-1-en-4-yn-3- one)]dicobalt (Co-Co) (2.6b):

O (OC)6Co2 O

Compound 2.6b was prepared according to General Procedure D, using compound 2.5b as starting material (0.0700 g, 0.304 mmol) with an excess amount of

Co2(CO)8. The product was isolated following column chromatography (15:1 petroleum

o ether : Et2O) as a red crystal (0.1091 g, 0.212 mmol, 70 % yield), m.p. 64-66 C; IR nmax

-1 1 3006, 2962, 2924, 2840, 2099, 2008, 1630, 1580 cm ; H NMR (CDCl3) d 6.65 (d, J=2.4,

2H), 6.454 (t, J=2.4, 1H), 5.86 (s, 1H), 5.81 (d, J=1.5, 1H), 3.79 (s, 6H), 2.05 (d, J=0.9,

13 3H); C NMR (CDCl3) 198.4 (broad), 194.9, 161.1, 144.1, 138.9, 126.4, 108.1, 100.6,

+ 92.0, 85.8, 55.5, 18.6; HRMS m/e for C20H14Co2O9 [M ] calculated 516.9380, found

516.9380.

128 Synthesis of hexacarbonyl[µ-h4-(2,4-dimethoxy-6-methyl-5,6-dihydro-8,9-dehydro-

5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7b):

Co2(CO)6 O O

Compound 2.7b was prepared according to General Procedure E, using compound 2.6b as starting material (0.0671 g, 0.130 mmol). After 24 h, the product was isolated following column chromatography (20:1 petroleum ether : Et2O) as a red crystal (

o 0.0374 g, 0.072 mmol, 56 % yield), m.p. 67-70 C; IR nmax 3003, 2924, 2850, 2097, 2025,

-1 1 2004, 1727, 1677, 1605, 1567 cm ; H NMR (CDCl3) d 6.87 (6, J=2.4, 1H), 6.52 (d, J=2.4,

1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.21 (d, J=15.9, 1H), 2.81 (m, 1H), 2.64 (m, 1H), 1.27 (s,

13 3H); C NMR (CDCl3) 205.3, 198.3 (broad), 159.8, 157.9, 137.7, 120.5, 108.8, 99.5, 88.0,

+ 78.2, 56.0, 55.4, 45.8, 28.2, 16.4; HRMS m/e for C20H14Co2O9 [M ] calculated 516.9380, found 516.9373.

129 Synthesis of 2-methyl-5-(3,4,5-trimethoxyphenyl)pent-1-en-4-yn-3-ol (2.4c):

O O

Compound 2.4c was prepared according to General Procedure A, using 5-ethynyl-

1,2,3-trimethoxybenzene (2.3c) as starting material (0.7147 g, 3.718 mmol) and methacrolein (2 equiv, 0.52 g, 0.62 mL, 7.4 mmol). The product was isolated following column chromatography (2:1 hexane : Et2O) as a white crystal (0.794 g, 3.031 mmol, 56

o % yield), m.p. 103-106 C; IR nmax 3434 (broad), 3010, 2971, 2945, 2876, 2842, 1577,

-1 1 1501 cm ; H NMR (CDCl3) d 6.67 (s, 2H), 5.24 (s, 1H), 5.01 (d, J=5.4, 1H), 4.97 (s, 1H),

13 3.83 (s, 9H), 2.26 (s (broad), 1H), 1.93 (s, 3H); C NMR (CDCl3) 152.9, 143.9, 138.8,

+ 117.4, 112.5, 108.8, 87.0, 85.7, 66.6, 60.9, 56.0, 18.2; HRMS m/e for C15H18O4 [M ] calculated 262.1205, found 262.1207.

130 Synthesis of 2-methyl-5-(3,4,5-trimethoxyphenyl)pent-1-en-4-yn-3-one (2.5c):

O O

Compound 2.5c was prepared according to General Procedure B, using compound

2.4c as starting material (0.1531 g, 0.583 mmol) with PDC powder (1.5 equiv, 0.3289 g,

0.874 mmol). The product was isolated following column chromatography (1:1 petroleum

o ether : Et2O) as a yellow solid (0.1289 g, 0.495 mmol, 85 % yield), m.p. 99-101 C; IR nmax

-1 1 3002, 2934, 2837, 2195, 1639, 1623, 1573, 1500 cm ; H NMR (CDCl3) d 6.81 (s, 2H),

6.51 (d, J=0.9, 1H), 6.06 (d, J=0.9, 1H), 3.83 (s, 3H), 3.82 (s, 6H), 1.94 (s, 3H); 13C NMR

(CDCl3) 180.2, 153.3, 145.3, 140.9, 130.8, 115.0, 110.3, 91.9, 85.5, 61.1, 56.4, 16.3;

+ + HRMS m/e for C15H16O4 [M +H ] calculated 261.1127, found 261.1133.

131 Synthesis of hexacarbonyl[µ-h4 (2-methyl-5-(3,4,5-trimethoxyphenyl)pent-1-en-4-yn-

3-one)]dicobalt (Co-Co) (2.6c):

O (OC)6Co2 O

O O

Compound 2.6c was prepared according to General Procedure D, using compound 2.5c as starting material (0.0900 g, 0.346 mmol) with an excess amount of

Co2(CO)8. The product was isolated following column chromatography (1:1 petroleum

o ether : Et2O) as red crystals (0.1570 g, 0.287 mmol, 83 % yield), m.p. 65-68 C; IR nmax

-1 1 3012, 2954, 2932, 2831, 2094, 2067, 2016, 1620, 1573 cm ; H NMR (CDCl3) d 6.76 (s,

13 2H), 5.92 (s, 1H), 5.84 (s, 1H), 3.89 (s, 3H), 3.84 (s, 6H), 2.07 (s, 3H); C NMR (CDCl3)

198.4 (broad), 195.1, 153.5, 144.5, 138.5, 132.1, 125.9, 107.2, 92.8, 85.3, 60.9, 56.2, 18.6;

+ HRMS m/e for C21H16Co2O10 [M ] calculated 546.9485, found 546.9489.

132 Synthesis of hexacarbonyl[µ-h4-(1,2,3-trimethoxy-8-methyl-8,9-dihydro-5,6- dehydro-5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7c):

Co2(CO)6 O O O O

Compound 2.7c was prepared according to General Procedure E, using compound

2.6c as starting material (0.0651 g, 0.119 mmol). After stirring 12 h, the product was isolated following column chromatography (1:1 petroleum ether : Et2O) as red crystals

o (0.0454 g, 0.083 mmol, 70 % yield), m.p. 77-80 C; IR nmax 2968, 2936, 2096, 2057, 2010,

-1 1 1680, 1578, 1557 cm ; H NMR (CDCl3) d 7.05 (s, 1H), 3.94 (s, 6H), 3.90 (s, 3H), 3.13

13 (d, J=15.9, 1H), 2.78 (m, 2H), 1.27 (d, J=6.9, 3H); C NMR (CDCl3) 204.9, 198.4 (broad),

153.0, 151.6, 143.4, 131.4, 126.1, 111.9, 88.0, 78.1, 61.5, 60.9, 56.0, 45.8, 29.1, 16.5;

+ HRMS m/e for C21H16Co2O10 [M ] calculated 546.9485, found 546.9495.

133 Synthesis of 1-(3,5-dimethoxyphenyl)-5-methyl-4-methylenehex-1-yn-3-ol (2.4d):

Following General Procedure A, 1-ethynyl-3,5-dimethoxybenzene 2.3b (0.5407 g, 3.333 mmol) was used with 3-methyl-2-methylidenebutanal (2 equiv, 0.6500 g, 0.80 mL, 6.700 mmol). The product was isolated following column chromatography (5:1 petroleum ether : Et2O) as a yellow viscous oil (0.7118 g, 2.734 mmol, 82 % yield). IR nmax

-1 1 3436 (broad), 2962, 2873, 2841, 2250, 1588 cm ; H NMR (CDCl3) d 6.58 (d, J=2.4, 2H),

6.44 (t, J=2.4, 1H), 5.39 (s, 1H), 5.09 (d, J=6.1, 1H), 5.04 (s, 1H), 3.76 (s, 6H), 2.59 (m,

13 1H), 2.32 (d, J=6.3, 1H), 1.14 (d, J=6.9, 6H); C NMR (CDCl3) 160.6, 154.8, 124.0, 109.6,

+ 107.0, 101.9, 88.3, 85.8, 65.4, 55.5, 30.3, 22.8; HRMS m/e for C16H20O3 [M ] calculated

260.1412, found 260.1414.

134 Synthesis of 1-(3,5-dimethoxyphenyl)-5-methyl-4-methylenehex-1-yn-3-one (2.5d):

Compound 2.5d was prepared according to General Procedure B, by the reaction of compound 2.4d as starting material (0.1264 g, 0.485 mmol) with PDC powder (1.5 equiv, 0.2738 g, 0.728 mmol). After 12 h, the product was isolated following column chromatography (5:1 petroleum ether : Et2O) as a yellow oil (0.1170 g, 0.453 mmol, 93 %

-1 1 yield). IR nmax 2962, 2873, 2841, 2197, 1637, 1586 cm ; H NMR (CDCl3) d 6.72 (d,

J=2.1, 2H), 6.59 (s, 1H), 6.54 (t, J=2.1, 1H), 6.03 (s, 1H), 3.79 (s, 6H), 2.97 (m, 1H), 1.08

13 (d, J=6.9, 6H); C NMR (CDCl3) 179.8, 160.6, 155.6, 128.2, 121.4, 110.4, 103.8, 90.9,

+ + 85.8, 55.5, 27.0, 21.8; HRMS m/e for C16H18O3 [M +H ] calculated 259.1334, found

259.1334.

135 Synthesis of hexacarbonyl[µ-h4 (1-(3,5-dimethoxyphenyl)-5-methyl-4-methylenehex-

1-yn-3-one)]dicobalt (Co-Co) (2.6d):

O (OC)6Co2

Compound 2.6d was prepared according to General Procedure D, using compound 2.5d as starting material (0.1091 g, 0.422 mmol) and an excess amount of

Co2(CO)8. The product was isolated as a dark red viscous oil (0.2036 g, 0.374 mmol, 89 %

-1 1 yield). IR nmax 2962, 2096, 2057, 2017, 1585 cm ; H NMR (CDCl3) d 6.65 (d, J=2.4,

2H), 6.46 (t, J=2.1, 1H), 5.82 (s, 1H), 5.64 (d, J=1.2, 1H), 3.79 (s, 6H), 3.08 (m, 1H), 1.09

13 (d, J=6.9, 6H); C NMR (CDCl3) 198.3 (broad), 195.6, 161.1, 155.4, 139.0, 121.4, 108.0,

+ 100.7, 92.4, 87.7, 55.5, 29.2, 21.6; HRMS m/e for C22H18Co2O9 [M ] calculated 544.9693, found 544.9693.

136 Synthesis of hexacarbonyl[µ-h4-(6-isopropyl-2,4-dimethoxy-5,6-dihydro-8,9- dehydro-5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7d):

Co2(CO)6 O O

Compound 2.7d was prepared according to General Procedure E, using compound 2.6d as starting material (0.1142 g, 0.209 mmol). After 4 h at 0 oC, the product was isolated following column chromatography (10:1 petroleum ether : Et2O) as dark red

o crystals (0.0978 g, 0.179 mmol, 86 % yield), m.p. 85-88 C; IR nmax 2960, 2871, 2838,

-1 1 2095, 2056, 2011, 1672 cm ; H NMR (CDCl3) d 6.85 (d, J=2.4, 1H), 6.52 (d, J=2.4, 1H),

3.85 (d, J=1.2, 6H), 3.18 (q, J=8.1, 1H), 2.81 (d, J=16.2, 1H), 2.47 (t, J=8.1, 1H), 1.77 (m,

13 1H), 0.92 (2d, 6H); C NMR (CDCl3) 205.2, 198.4 (broad), 159.8, 158.2, 138.3, 119.3,

108.7, 99.5, 87.1, 58.9, 56.1, 55.4, 27.6, 22.9, 20.9, 19.8; HRMS m/e for C22H18Co2O9

[M+] calculated 544.9693, found 544.9694.

137 Synthesis of 1-(3,5-dimethoxyphenyl)-4-methylenehex-1-yn-3-ol (2.4e):

Following General Procedure A, 1-ethynyl-3,5-dimethoxybenzene 2.3b (0.1217 g, 0.750 mmol) was used with 2-methylenebutanal (2 equiv, 0.15 mL, 1.5 mmol). The product was isolated following preparative chromatography (2:1 hexane : Et2O) as a colourless viscous oil (0.0886 g, 0.360 mmol, 48 % yield). IR nmax 3413, 2963, 2937, 2876,

-1 1 2840, 1589 cm ; H NMR (CDCl3) d 6.59 (d, J=2.4, 2H), 6.44 (t, J=2.1, 1H), 5.33 (t,

J=1.2, 1H), 5.05 (s, 1H), 4,99 (s, 1H), 3.77 (s, 6H), 2.29 (q, J=7.5, 2H), 1.98 ((br s), 1H),

13 1.14 (t, J=7.5, 3H); C NMR (CDCl3) 160.5, 149.7, 123.8, 110.4, 109.5, 101.9, 87.8, 85.8,

+ + 66.2, 55.4, 24.5, 12.2; HRMS m/e for C15H18O3 [M -H ] calculated 245.1178, found

245.1175.

138 Synthesis of 1-(3,5-dimethoxyphenyl)-4-methylenehex-1-yn-3-one (2.5e):

Compound 2.5e was prepared according to General Procedure B, using compound

2.4e as starting material (0.0992 g, 0.375 mmol) and the oxidation reagent PDC powder

(1.5 equiv, 0.2116 g, 0.562 mmol). After 12 h, the product was isolated following column chromatography (5:1 petroleum ether : Et2O) as a yellow oil (0.0839 g, 0.352 mmol, 94 %

-1 1 yield). IR nmax 2964, 2936, 2876, 2841, 2197, 1636 cm ; H NMR (CDCl3) d 6.73 (d,

J=2.4, 2H), 6.55 (m, 2H), 6.04 (s, 1H), 3.79 (s, 6H), 2.38 (q, J=7.5, 2H), 1.09 (t, J=7.5, 3H);

13 C NMR (CDCl3) 179.9, 160.7, 151.0, 129.3, 121.5, 110.5, 104.0, 91.1, 85.6, 55.5, 22.6,

+ 12.4; HRMS m/e for C15H16O3 [M ] calculated 245.1178, found 245.1185.

139 Synthesis of hexacarbonyl[µ-h4 (1-(3,5-dimethoxyphenyl)-4-methylenehex-1-yn-3- one)]dicobalt (Co-Co) (2.6e):

O (OC)6Co2

Compound 2.6e was prepared according to General Procedure D, using compound 2.5e as starting material (0.0446 g, 0.183 mmol) and an excess amount of

Co2(CO)8. The product was isolated as a dark red viscous oil (0.0737 g, 0.139 mmol, 76 %

-1 1 yield). IR nmax 2966, 2937, 2838, 2096, 2057, 2012, 1635, 1583 cm ; H NMR (CDCl3) d

6.65 (d, d=2.2, 2H), 6.46 (t, J=2.2, 1H), 5.85 (s, 1H), 5.72 (d, J=1.3, 1H), 3.79 (s, 6H), 2.47

13 (q, J=7.4, 2H), 1.09 (t, J=7.4, 3H); C NMR (CDCl3) 198.3 (broad), 194.9, 160.9, 150.3,

+ 138.9, 123.8, 107.9, 100.5, 92.0, 86.6, 55.4, 24.9, 12.6; HRMS m/e for C21H16Co2O9 [M ] calculated 530.9537, found 530.9537.

140 Synthesis of hexacarbonyl[µ-h4-(6-ethyl-2,4-dimethoxy-5,6-dihydro-8,9-dehydro-5H- benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7e):

Co2(CO)6 O O

Compound 2.7e was prepared according to General Procedure E, using compound

2.6e as starting material (0.1035 g, 0.195 mmol). After 12 h, the product was isolated following column chromatography (10:1 petroleum ether : Et2O) as dark red crystals

o (0.0775 g, 0.146 mmol, 75 % yield), m.p. 87-90 C; IR nmax 2963, 2938, 2877, 2840,

-1 1 2096, 2056, 2011, 1674, 1601 cm ; H NMR (CDCl3) d 6.86 (d, J=2.4, 1H), 6.51 (d, J=2.4,

1H), 3.85 (dd, J=3.8, 1.3, 6H), 2.97 (m, 2H), 2.62 (m, 1H), 1.73 (m, 1H), 1.41 (m, 1H),

13 0.95 (t, J=7.3, 3H); C NMR (CDCl3) 205.4, 198.3 (broad), 159.8, 158.1, 138.0, 119.8,

108.7, 99.4, 87.5, 77.9, 56.0, 55.4, 53.2, 25.2, 23.5, 11.8; HRMS m/e for C21H16Co2O9

[M+] calculated 530.9537, found 530.9540.

141 Synthesis of 2-benzyl-5-(3,5-dimethoxyphenyl)pent-1-en-4-yn-3-ol (2.4f):

OH Bn O

Following General Procedure A: 1-ethynyl-3,5-dimethoxybenzene 2.3b (0.1087 g, 0.670 mmol) was used with 2-benzylacrylaldehyde (2 equiv, 0.1958 g, 1.340 mmol).

The product was isolated following column chromatography (3:1 Hexane : Et2O) as a viscous yellow oil (0.1590 g, 0.515 mmol, 77 % yield). IR nmax 3372 (broad), 2924, 2842,

-1 1 1587, 1452 cm ; H NMR (CDCl3) d 7.28 (m, 5H), 6.59 (d, J=2.4, 2H), 6.46 (t, J=2.4,

13 1H), 5.46 (s, 1H), 5.00 (s, 1H), 4.95 (s, 1H), 3.78 (s, 6H), 3.61 (s, 2H); C NMR (CDCl3)

160.4, 147.4, 138.8, 129.2, 128.4, 126.3, 123.7, 113.7, 109.5, 101.9, 87.5, 86.3, 65.2, 55.4,

+ 38.8; HRMS m/e for C20H20O3 [M ] calculated 308.1412, found 308.1417.

142 Synthesis of 2-benzyl-5-(3,5-dimethoxyphenyl)pent-1-en-4-yn-3-one(2.5f):

O Bn O

Compound 2.5f was prepared according to General Procedure B, using compound

2.4f as starting material (0.1341 g, 0.434 mmol) and the oxidation reagent PDC powder

(1.5 equiv, 0.2449 g, 0.651 mmol). After 12 h, the product was isolated following column chromatography (5:1 hexane : Et2O) as a tan oil (0.0864 g, 0.282 mmol, 65 % yield). IR

-1 1 nmax 2964, 2936, 2876, 2841, 2197, 1636 cm ; H NMR (CDCl3) d 7.25 (m, 5H), 6.72 (d,

J=2.4, 2H), 6.65 (s, 1H), 6.55 (t, J=2.4, 1H), 5.90 (s, 1H), 3.79 (s, 6H), 3.69 (s, 2H); 13C

NMR (CDCl3) 179.4, 160.8, 149.1, 138.5, 131.8, 129.3, 128.6, 126.5, 121.4, 110.6, 104.1,

+ 91.7, 85.6, 55.6, 35.8; HRMS m/e for C20H18O3 [M ] calculated 306.1256, found 306.1257.

143 Synthesis of hexacarbonyl[µ-h4 (2-benzyl-5-(3,5-dimethoxyphenyl)pent-1-en-4-yn-3- one)]dicobalt (Co-Co) (2.6f):

O (OC)6Co2 Bn O

Compound 2.6f was prepared according to General Procedure D, using compound

2.5f as starting material (0.0751 g, 0.245 mmol) and an excess amount of Co2(CO)8. The product was isolated following column chromatography (10:1 petroleum ether : Et2O) as

o dark red crystals (0.1132 g, 0.191 mmol, 78 % yield), m.p. 58-60 C; IR nmax 3062, 3021,

-1 1 2967, 2921, 2840, 2094, 2058, 2037, 2005, 1637, 1623 cm ; H NMR (CDCl3) d 7.25 (m,

5H), 6.62 (d, J=2.4, 2H), 6.44 (t, J=2.1, 1H), 5.91 (s, 1H), 5.67 (s, 1H), 3.78 (s, 2H), 3.77

13 (s, 6H); C NMR (CDCl3) 198.2 (broad), 194.3, 161.1, 148.5, 138.9, 138.6, 129.1, 128.6,

+ 126.5, 125.8, 108.0, 100.7, 92.3, 86.3, 55.5, 38.3; HRMS m/e for C26H18Co2O9 [M ] calculated 592.9693, found 592.9694.

144 Synthesis of hexacarbonyl[µ-h4-(6-benzyl-2,4-dimethoxy-5,6-dihydro-8,9-dehydro-

5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7f):

Co2(CO)6 O O

Bn O

Compound 2.7f was prepared according to General Procedure E, using compound

2.6f as starting material (0.0481 g, 0.081 mmol). After 20 h, the product was isolated following column chromatography (5:1 petroleum ether : Et2O) as dark red crystals (0.0351

o g, 0.059 mmol, 73 % yield), m.p. 63-66 C; IR nmax 2922, 2850, 2097, 2058, 2017, 1728,

-1 1 1680, 1600 cm ; H NMR (CDCl3) d 7.20 (m, 5H), 6.84 (d, J=2.4, 1H), 6.41 (d, J=2.4,

13 1H), 3.83 (s, 3H), 3.57 (s, 3H), 3.25 (m, 2H), 2.97 (m, 1H), 2.63 (m, 2H); C NMR (CDCl3)

205.4, 198.2 (broad), 159.9, 158.0, 139.5, 137.9, 129.3, 128.3, 126.2, 120.4, 108.7, 99.6,

+ 88.1, 83.5, 55.9, 55.4, 52.9, 36.2, 25.1; HRMS m/e for C26H18Co2O9 [M ] calculated

592.9693, found 592.9695.

145 Synthesis of 5-(3,5-dimethoxyphenyl)-2-(triisopropylsilyl)pent-1-en-4-yn-3-ol(2.4g):

OH TIPS O

Compound 2.4g was prepared according to General Procedure A. 1-ethynyl-3,5- dimethoxybenzene 2.3b as starting material (0.0707 g, 0.692 mmol) was used with 2-

(triisopropylsilyl)acrylaldehyde (2 equiv, 6.516 g, 1.384 mmol). The product was isolated following column chromatography (5:1 Hexane : Et2O) as a yellow oil (0.0553 g,

-1 0.148 mmol, 34 % yield). IR nmax 3420 (broad), 2941, 2864, 1588, 1458, 1419, 1383 cm ;

1 H NMR (CDCl3) d 6.60 (d, J=2.4, 2H), 6.44 (m, 2H), 5.63 (m, 1H), 5.21 (s, 1H), 3.78 (s,

13 6H), 1.29 (m, 4H), 1.12 (d, J=6.9, 18H); C NMR (CDCl3) 160.4, 146.5, 129.0, 124.0,

+ + 109.4, 101.7, 88.8, 86.4, 65.5, 55.4, 18.8, 11.3; HRMS m/e for C22H34O3Si [M +H ] calculated 375.2355, found 375.2344.

146 Synthesis of hexacarbonyl[µ-h4 (5-(3,5-dimethoxyphenyl)-2-(triisopropylsilyl)pent-1- en-4-yn-3-one)]dicobalt (Co-Co) (2.6g):

O (OC) Co 6 2 TIPS O

To a solution of alcohol 2.4g (0.0823 g, 0.219 mmol) in anhydrous CH2Cl2 at room temperature was added PDC powder (1.5 equiv, 0.1234 g, 0.328 mmol), and allowed the

o reaction was stirred for 16 h. After this time, an excess amount of Co2(CO)8 at 0 C and allowed to stir for 10 h. The mixture was treated following General Procedure D. The product was isolated following preparative chromatography (25:1 Hexane : Et2O) as dark

o red crystals (0.0833 g, 0.126 mmol, 69 % yield), m.p. 108-110 C; IR nmax 2937, 2864,

-1 1 2092, 2053, 2020, 1621, 1575 cm ; H NMR (CDCl3) d 6.67 (d, J=2.2, 2H), 6.53 (d, J=1.6,

1H), 6.47 (t, J=2.2, 1H), 6.20 (d, J=1.6, 1H), 3.79 (s, 6H), 1.38 (m, 3H), 1.10 (d, J=7.5,

13 18H); C NMR (CDCl3) 199.5, 198.4 (broad), 160.9, 149.4, 139.2, 138.9, 107.7, 100.6,

+ 93.2, 88.0, 55.3, 18.7, 11.2; HRMS m/e for C28H32Co2O9Si [M ] calculated 659.0558, found 659.0549.

147 Synthesis of hexacarbonyl[µ-h4-(6-(triisopropylsilyl)-2,4-dimethoxy-5,6-dihydro-8,9- dehydro-5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7g):

Co2(CO)6 O O

TIPS O

Compound 2.7g was prepared according to General Procedure E, using compound 2.6g as starting material (0.0831 g, 0.126 mmol). After 30 minutes at 0 oC, the product was isolated following column chromatography (40:1 petroleum ether : Et2O) as

o dark red crystals (0.0736 g, 0.112 mmol, 89 % yield), m.p. 112-114 C; IR nmax 2942, 2866,

-1 1 2096, 2057, 2016, 1673, 1600 cm ; H NMR (CDCl3) d 6.85 (d, J=2.4, 1H), 6.49 (d, J=2.4,

1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.72 (d, J=15.0, 1H), 2.44 (m, 2H), 1.44 (m, 3H), 1.12 (dd,

13 J=7.5, 3.0, 18H); C NMR (CDCl3) 205.5, 198.5 (broad), 159.8, 157.4, 138.2, 122.7,

108.6, 99.1, 88.1, 77.3, 55.7, 55.4, 40.8, 22.6, 19.3, 19.2, 11.8; HRMS m/e for

+ C28H32Co2O9Si [M ] calculated 659.0558, found 659.0562.

148 Synthesis of (E)-1-(3,5-dimethoxyphenyl)-4-methylhex-4-en-1-yn-3-ol (2.4h):

Following General Procedure A: alkyne 2.3b (0.1148 g, 0.708 mmol) was used with tiglic aldehyde ((E)-2-methylbut-2-enal) (2 equiv, 0.12 g, 0.14 mL, 1.0 mmol). The crude yellow oil was obtained and purified by radial chromatography (5:1 hexanes : Et2O) to yield pure product 2.4h, as a dark yellow viscous oil (0.1521 g, 0.617 mmol, 87 % yield);

-1 1 IR nmax 3414 (broad), 2959, 2935, 2200, 1690, 1647, 1589, 1454, 1420 cm ; H NMR

(CDCl3) d 6.59 (d, J=2.4, 2H), 6.43 (t, J=2.1, 1H), 5.77 (m, 1H), 4.96 (s, 1H), 3.77 (s, 6H),

13 1.81 (s, 3H), 1.67 (dd, J=6.6, 0.9, 3H); C NMR (CDCl3) 160.6, 135.0, 124.0, 123.0, 109.6,

+ 102.0, 88.1, 86.0, 68.7, 55.5, 13.4, 12.2; HRMS m/e for C15H18O3 [M ] calculated

246.1256, found 246.1247.

149 Synthesis of hexacarbonyl[µ-h4 ((E)-1-(3,5-dimethoxyphenyl)-4-methylhex-4-en-1- yn-3-one)]dicobalt (Co-Co) (2.6h E-):

Synthesis of hexacarbonyl[µ-h4 ((E)-6-(3,5-dimethoxyphenyl)-3-methylhex-3-en-5- yn-2-one)]dicobalt (Co-Co) (2.6h¢):

According to General Procedure B, alcohol 2.4h (0.2051 g, 0.948 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) and (1.5 equiv, 0.5351 g, 1.422 mmol) of PDC was added. Afterward, the crude material was dissolved in anhydrous CH2Cl2 (20 mL) and an excess amount of Co2(CO)8 was added to this solution following General Procedure

D. The reaction was stirred while maintaining the temperature at 0 oC. After 2 h, the mixture was concentrated under reduced pressure in a cold water bath, obtaining a dark red material. This crude material was purified first on a plug of silica, first washing with 100% petroleum ether to remove the remaining Co2(CO)8, followed by a second washing with

100% Et2O to obtain the product complexes. Column chromatography (1:1 petroleum ether

: Et2O) gave 66 % yield of two different isomers (2.6h E-) as a major product (elute first) and a minor product (2.6h¢).

O (OC)6Co2 O

(2.6h E-) (0.1421 g, 0.674 mmol, 48 % yield) IR nmax 3005, 2938, 2838, 2095,

-1 1 2054, 2009, 1625, 1583 cm ; H NMR (CDCl3) d 6.72 (apparent qd, J=7.0, 1.2, 1H), 6.66

150 (d, J=2.4, 2H), 6.46 (t, J=2.1, 1H), 3.79 (s, 6H), 1.95 (d, J=0.9, 3H), 1.77 (dd, J=6.7, 0.9,

3H); NOESY-2D NMR (300 MHz, CDCl3): an off diagonal cross peak correlating the d

13 1.77 and d 1.95 resonances; C NMR (CDCl3) 198.5 (broad), 194.6, 161.1, 139.8, 139.2,

+ 137.6, 108.1, 100.7, 91.9, 86.7, 55.5, 14.6, 12.1 HRMS m/e for C21H16Co2O9 [M ] calculated 530.9537, found 530.9531.

O (OC)6Co2 O

o (2.6h¢) (0.0745 g, 0.254 mmol, 18 % yield), m.p. 88-91 C; IR nmax 2961, 2932,

-1 1 2838, 2089, 2055, 2016, 2004, 1665 cm ; H NMR (CDCl3) d 7.73 (d, J=1.5, 1H), 6.62

(d, J=2.1, 2H), 6.45 (t, J=2.4, 1H), 3.80 (s, 6H), 2.44 (s, 3H), 1.90 (d, J=1.2, 3H); 13C NMR

(CDCl3) 198.5 (broad), 194.6, 161.1, 139.8, 139.2, 137.6, 108.1, 100.7, 91.9, 86.7, 55.5,

+ 14.6, 12.1 HRMS m/e for C21H16Co2O9 [M ] calculated 530.9537, found 530.9529.

151 Synthesis of hexacarbonyl[µ-h4-(2,4-dimethoxy-5,6-dimethyl-5,6-dihydro-8,9- dehydro-5H-benzo[7]annulen-7(6H)-one)]dicobalt (Co-Co) (2.7h):

Synthesis of (E)-1-(3,5-dimethoxyphenyl)-4-methylhex-4-en-1-yn-3-one (2.5h):

Co2(CO)6 O O

Compound 2.7h was prepared according to General Procedure E, using E- 2.6h as starting material (0.0812 g, 0.153 mmol). After 7 days, the product was isolated following column chromatography (10:1 petroleum ether : Et2O) as dark red viscous oil in very low yield (0.009 g, 0.017 mmol, 12 % yield (33 % brsm)) eluted first and 17 % yield of the decomplexed starting material 2.5h. IR nmax = 2923, 2853, 2201, 2095, 2060, 2030

-1 1 cm ; H NMR (CDCl3) d = 6.89 (d, J=2.4, 1H), 6.49 (d, J=2.4, 1H), 3.83 (d, J=2.4, 6H),

13 3.57 (m, 1H), 3.11 (m, 1H), 1.30 (d, J=6.9, 3H), 0.92 (d, J=7.5, 3H); C NMR (CDCl3)

204.3, 198.3 (broad), 159.8, 157.9, 137.7, 120.4, 107.7, 99.5, 88.0, 78.2, 56.0, 55.4, 45.8,

+ 28.2, 18.2, 16.4; HRMS m/e for C21H16Co2O9 [M ] calculated 530.9537, found 530.9539.

152 O

-1 1 Compound 2.5h-E: IR nmax = 2926, 2844, 2199, 1623, 1591cm ; H NMR (CDCl3) d = 7.32 (q, J=6.9, 1H), 6.73 (d, J=2.4, 2H), 6.54 (d, J=2.1, 1H), 3.79 (s, 6H), 1.98 (d, J=6.9,

3H), 1.86 (s, 3H); NOESY-2D NMR (300 MHz, CDCl3): an off diagonal cross peak

13 correlating the d 1.86 and d 1.98 resonances; C NMR (CDCl3) 180.2, 160.6, 145.3, 139.6,

+ + 121.8, 110.4, 103.7, 90.9, 85.4, 55.5, 15.2, 10.3; HRMS m/e for C15H16O3 [M +H ] calculated 245.1178, found 245.1179.

Synthesis of 2-methyl-5-(1-methyl-1H-indol-2-yl)pent-1-en-4-yn-3-ol (2.12):

General Procedure G: Compound 2.12 was prepared using a Sonogashira coupling reaction. In a two nicked round bottom flask, 2-iodo-1-methyl-1H-indole 2.10

(0.5637g, 2.193 mmol) and synthesized 5-(trimethylsilyl)pent-1-en-4-yn-3-ol 2.11183b

(1.02 equiv, 0.3764 g, 2.443 mmol) were dissolved in degassed THF (3.5 mL).

Triethylamine (Et3N) (10 mL). Pd(PPh3)4 (0.0800 g, 0.066 mmol, 3 mol%) and CuI (0.0250 g, 0.109 mmol, 5 mol%) were added under N2. TBAF (1.15 equiv, 2.5 mL) was added dropwise to the reaction flask. The reaction was allowed to stir for 14 hours at room

Ò temperature. After this time, the reaction was filtered through Celite , dissolved in Et2O

153 (60 mL), and extracted with NH4Cl (aq., sat., 2 C 60 mL), followed by brine (1 C 60 mL).

The organic fraction was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Column chromatography (2:1 hexane : Et2O) eluted the product 2.12

o (0.4303 g, 1.909 mmol, 87 % yield), as a dark yellow solid, m.p. 70-72 C; IR nmax 3360

-1 1 (broad), 3056, 2974, 2942, 2918, 2878, 2225, 2061, 2027 cm ; H NMR (CDCl3) d 7.60

(dd, J=4.8, 0.3, 1H), 7.28 (d, J=2.4, 2H), 7.14 (m, 1H), 6.79 (s, 1H), 5.31 (s, 1H), 5.13 (d,

13 J=3.6, 1H), 5.05 (s, 1H), 3.81 (s, 3H), 2.19 (m, 1H), 1.99 (s, 3H); C NMR (CDCl3) 143.6,

137.1, 126.9, 123.1, 121.1, 120.9, 120.1, 112.9, 109.4, 107.8, 94.0, 77.7, 66.8, 30.6, 18.2;

+ + HRMS m/e for C15H15NO [M +H ] calculated 226.1232, found 226.1232.

Synthesis of 2-methyl-5-(1-methyl-1H-indol-2-yl)pent-1-en-4-yn-3-one (2.13):

Compound 2.13 was prepared according to General Procedure B, by the reaction of compound 2.12 as starting material (0.2201 g, 0.976 mmol) and PDC powder (1.5 equiv,

0.5507 g, 1.464 mmol). The product was isolated following column chromatography (1:1 petroleum ether : Et2O) as a yellow oil (0.1307 g, 0.585 mmol, 60 % yield). IR nmax 2954,

-1 1 2920, 2852, 2181, 1622, 1516 cm ; H NMR (CDCl3) d 7.62 (d, J=8.9, 1H), 7.32 (m, 2H),

7.15 (m, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 6.10 (s, 1H), 3.88 (s, 3H), 1.99 (s, 3H); 13C NMR

(CDCl3) 179.4, 145.2, 138.2, 130.1, 126.8, 124.8, 121.7, 120.7, 118.8, 112.5, 109.8, 93.3,

+ + 84.0, 30.9, 16.3; HRMS m/e for C15H13NO [M +H ] calculated 224.1075, found

224.1081.

154 Synthesis of hexacarbonyl[µ-h4 (2-methyl-5-(1-methyl-1H-indol-2-yl)pent-1-en-4-yn-

3-one)]dicobalt (Co-Co) (2.14):

Co2(CO)6 O

Compound 2.14 was prepared according to General Procedure D, using compound 2.13 (0.1210 g, 0.542 mmol) with an excess amount of Co2(CO)8. The product was isolated following column chromatography (1:1 petroleum ether : Et2O) as a dark

o green crystals (0.2590 g, 0.508 mmol, 94 % yield), m.p. 134-137 C; UV-vis (CHCl3) lmax

-1 -1 - = 598 nm, e = 1199 M cm ; IR nmax 2934, 2512, 2194, 2142, 2094, 2059, 2019, 1617 cm

1 1 ; H NMR (CDCl3) d 7.61 (d, J=8.9, 1H), 7.30 (m, 2H), 7.15 (m, 1H), 6.86 (s, 1H), 5.83

13 (s, 2H), 3.72 (s, 3H), 2.10 (d, J=0.6, 3H); C NMR (CDCl3) 198.5 (broad), 195.0, 144.3,

139.0, 134.2, 128.0, 126.3, 123.4, 121.0, 120.7, 109.6, 108.0, 78.1, 77.3, 30.7, 18.6; HRMS

+ m/e for C21H13Co2NO7 [M ] calculated 509.9434, found 509.9436.

155 Synthesis of hexacarbonyl[µ-h4-(5,9-dimethyl-9,10-dihydro-6,7- dehydrocyclohepta[b]indole-8(5H)-one)]dicobalt (Co-Co) (2.15):

N Co2(CO)6

Compound 2.15 was prepared according to General Procedure E, using compound 2.14 (0.0789 g, 0.155 mmol). After 48 h, the product was isolated following column chromatography (20:1 petroleum ether : Et2O) as a dark green solid (0.0513 g,

o - 0.101 mmol, 65 % yield), m.p. >150 C; IR nmax 2924, 2859, 2094, 2046, 2009, 1664 cm

1 1 ; H NMR (CDCl3) d 7.56 (d, J=1.2, 1H), 7.33 (q, J=6.9, 2H), 7.15 (m, 1H), 3.93 (s, 3H),

3.15 (dd, J=16.5, 2.1, 1H), 3.03 (m, 1H), 2.79 (dd, J=16.5, 11.1 ,1H), 1.37 (d, J=6.6, 3H);

13 C NMR (CDCl3) 204.8, 198.0 (broad), 138.8, 132.5, 126.6, 123.6, 120.1, 119.2, 115.2,

+ 109.4, 86.4, 72.4, 43.8, 29.9, 29.4, 16.4; HRMS m/e for C21H13Co2NO7 [M ] calculated

509.9434, found 509.9428.

156 Synthesis of 5-(cyclohex-1-en-1-yl)-2-methylpent-1-en-4-yn-3-ol (2.21a):

Compound 2.21a was prepared according to General Procedure A. 1- ethynylcyclohex-1-ene 2.20 as starting material (0.60 g, 0.66 mL, 5.6 mmol) was used with methacrolein (2 equiv, 0.79 g, 0.93 mL, 11 mmol). The product was isolated following column chromatography (5:1 Hexane : Et2O) as a clear to yellowish oil (0.4881 g, 2.769

- mmol, 49 % yield). IR nmax 3348 (broad), 3080, 2931, 2863, 2186, 1711, 1647, 1614 cm

1; 1H NMR d 6.11 (m, 1H), 5.15 (s, 1H), 4.90 (m, 2H), 2.08 (m, 4H), 1.86 (s, 3H), 1.56 (m,

4H); 13C NMR 144.5, 135.4, 112.2, 111.1, 87.6, 85.6, 66.6, 29.2, 25.7, 22.3, 21.5, 18.2;

+ + HRMS m/e for C12H16O [M -H ] calculated 175.1123, found 175.1126.

157 Synthesis of 5-(cyclohex-1-en-1-yl)-2-methylpent-1-en-4-yn-3-one (2.22a):

Compound 2.22a was prepared according to General Procedure B, using compound 2.21a as starting material (0.4440 g, 2.521 mmol) and PDC powder (1.5 equiv,

1.4226 g, 3.781 mmol). After 12 h, the product was isolated following column chromatography (5:1 hexane : Et2O) as a yellow oil (0.3134 g, 1.789 mmol, 71 % yield).

-1 1 IR nmax 2930, 2865, 2184, 1635, 1617 cm ; H NMR (CDCl3) d 6.46 (m, 1H), 6.39 (m,

13 1H), 5.97 (t, J=1.2, 1H), 2.18 (m, 4H), 1.91 (s, 3H), 1.64 (m, 4H); C NMR (CDCl3) 180.5,

145.4, 141.9, 130.2, 119.2, 94.1, 84.4, 28.5, 26.2, 22.1, 21.2, 16.4; HRMS m/e for C12H14O

[M+] calculated 175.1123, found 175.1124.

Synthesis of hexacarbonyl[µ-h4 (5-(cyclohex-1-en-1-yl)-2-methylpent-1-en-4-yn-3- one)]dicobalt (Co-Co) (2.23a):

O (OC)6Co2

Compound 2.23a was prepared according to General Procedure D, using compound 2.22a as starting material (0.0820 g, 0.470 mmol) and an excess amount of

Co2(CO)8. The product was isolated following column chromatography (10:1 petroleum

158 o ether : Et2O) as dark red crystals (0.1732 g, 0.376 mmol, 80 % yield), m.p. 76-78 C; IR

-1 1 nmax 2931, 2861, 2091, 2003, 1765, 1625, 1579 cm ; H NMR (CDCl3) d 6.21 (m, 1H),

5.86 (s, 1H), 5.83 (m, 1H), 2.21 (m, 2H), 2.16 (m, 2H), 2.02 (d, J=0.3, 3H), 1.72 (m, 4H);

13 C NMR (CDCl3) 198.9 (broad), 194.9, 144.7, 134.1, 131.9, 125.4, 96.7, 86.6, 30.8, 26.5,

+ 23.1, 22.0, 18.5; HRMS m/e for C18H14Co2O7 [M ] calculated 460.9482, found 460.9482.

Synthesis of hexacarbonyl[µ-h4-( 6-methyl-3,4,5,6-tetrahydro-8,9-dehydro-1H- benzo[7]annulen-7(2H)-one)]dicobalt (Co-Co) (2.24a, 2.24a¢):

Compound 2.24a,a¢ were prepared according to General Procedure E, using 2.23a as starting material (0.1004 g, 0.218 mmol). After 12 h, the product was isolated following column chromatography (50:1 hexane : Et2O) as dark red viscous oil (0.0442 g, 0.0958 mmol) 44 % yield. 2.24a¢ eluted first.

Co2(CO)6

-1 1 (2.24a, 29 % yield) IR nmax 2924, 2094, 2035, 2014, 1679 cm ; H NMR (CDCl3) d 2.77 (m, 1H), 2.32 (m, 2H), 1.70 (m, 4H), 1.27 (m, 4H), 1.18 (d, J=6.9, 3H); 13C NMR

(CDCl3) 203.8, 198.9 (broad), 141.8, 130.5, 91.7, 82.4, 38.2, 33.9, 33.7, 29.8, 22.9, 22.7,

+ + 19.3; HRMS m/e for C18H14Co2O7 [M +H ] calculated 460.9482, found 460.9482.

159 Co2(CO)6

-1 1 (2.24a¢, 15 % yield) IR nmax 2956, 2922, 2854, 2094, 2057, 2024, 1726 cm ; H

NMR (CDCl3) d 6.43 ((br s), 1H), 3.63 (m, 1H), 2.85 (m, 2H), 2.62 (m, 1H), 2.15 (m, 2H),

13 1.93 (m, 2H), 1.80 (m, 2H), 1.22 (d, J=6.8, 3H); C NMR (CDCl3) 204.7, 198.9 (broad),

143.8, 136.5, 91.7, 82.4, 38.2, 33.9, 33.7, 29.8, 22.9, 22.7, 19.3; HRMS m/e for

+ + C18H14Co2O7 [M +H ] calculated 460.9482, found 460.9480.

Synthesis of 5-(cyclohex-1-en-1-yl)-2-(triisopropylsilyl)pent-1-en-4-yn-3-ol (2.21b):

OH TIPS

Following General Procedure A: 1-ethynylcyclohexene 2.20 (3 equiv, 0.18 mL,

1.5 mmol) was used with 2-triisopropylsilylacrolein (0.0986 g, 0.464 mmol). Preparative

TLC (20:1 hexane : Et2O) afforded compound 2.21b as a colourless viscous liquid (0.0597

-1 1 g, 0.187 mmol, 40 % yield). IR nmax 3401 (broad), 2930, 2864, 2214, 1698, 1459 cm ; H

NMR (CDCl3) d 6.35 (t, J=1.5, 1H), 6.10 (m, 1H), 5.56 (d, J=1.5, 1H), 5.09 (s, 1H), 2.10

(m, 4H), 1.85 ((br s), 1H), 1.60 (m, 4H), 1.25 (m, 3H), 1.09 (d, J=6.9, 18H); 13C NMR

(CDCl3) 146.8, 135.1, 128.6, 120.2, 88.4, 86.5, 65.5, 29.0, 25.6, 22.2, 21.4, 18.8, 11.2;

+ + HRMS m/e for C20H34OSi [M -H ] calculated 317.2301, found 317.2292.

160 Synthesis of hexacarbonyl[µ-h4 (5-(cyclohex-1-en-1-yl)-2-(triisopropylsilyl)pent-1-en-

4-yn-3-one)]dicobalt (Co-Co) (2.23b):

O (OC) Co 6 2 TIPS

Alcohol 2.21b (0.0492 g, 0.154 mmol) was dissolved in anhydrous CH2Cl2 and (1.5 equiv, 0.0869 g, 0.231 mmol) of PDC was added and allowed to stir overnight, the solution was stirred for overnight. Then an excess amount of Co2(CO)8 was added to this solution.

The reaction was stirred while maintaining the temperature at 0 oC. After 2 h, the mixture was treated following General Procedure D. Preparative chromatography (15:1 hexane :

o Et2O) gives (0.0558 g, 0.093 mmol, 60 % yield), m.p. 58-60 C; IR nmax 2928, 2865, 2093,

2055, 2019 cm-1; 1H NMR d 6.53 (m, 1H), 6.22 (s, 2H), 2.26 (m, 2H), 2.17 (m, 2H), 1.75

(m, 4H), 1.36 (m, 3H), 1.10 (d, J=6.9, 18H); 13C NMR 199.5, 198.9 (broad), 150.1, 137.9,

134.1, 131.3, 97.9, 88.8, 30.8, 26.3, 22.9, 21.9, 18.7, 11.2; HRMS m/e for C26H32Co2O7Si

[M++H+] calculated 603.0660, found 603.0665.

161 Synthesis of hexacarbonyl[µ-h4-( 6-(triisopropylsilyl)-3,4,5,6-tetrahydro-8,9- dehydro-1H-benzo[7]annulen-7(2H)-one)]dicobalt (Co-Co) (2.24b, 2.24b′):

Co2(CO)6

TIPS

Compound 2.24b,b′ was prepared according to General Procedure E, using 2.23b as starting material (0.0500 g, 0.083 mmol). After 4 h at 0 oC, the product was isolated following column chromatography (50:1 hexane : Et2O) as dark red viscous oil (0.0311 g,

0.051 mmol, 62 % yield eluted second (80 % yield (brsm)). IR nmax 2940, 2891, 2864,

-1 1 2094, 2050, 2008 cm ; H NMR (CDCl3) d 2.52 (m, 4H), 2.27 (m, 2H), 1.74 (m, 4H),

13 1.39 (m, 4H), 1.10 (d, J=6.9, 18H); C NMR (CDCl3) 204.8, 198.9 (broad), 142.9, 129.3,

91.7, 82.4, 38.2, 33.9, 33.7, 29.8, 22.9, 22.7, 19.3, 11.5; HRMS m/e for C26H32Co2O7Si

[M++H+] calculated 603.0660, found 603.0653.

162 Synthesis of 6-isopropyl-2,4-dimethoxy-8-(triethylsilyl)-5H-benzo[7]annulen-7(6H)- one (2.28)

SiEt3 O O

Compound 2.7d (0.1019 g, 0.187 mmol) was dissolved in degassed 1,2- dichloroethane (3 mL). To this stirred solution, bis(trimethylsilyl)acetylene (0.088 mL,

0.374 mmol) and triethylsilane (0.14 mL, 0.898 mmol) were added. The reaction was

o placed in an oil bath set at 65 C for 4 h under N2. After this time, the mixture was allowed to cool down, dissolved in Et2O (60 mL) and extracted with H2O (3 C 60 mL). The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure.

Preparative TLC (5:1 petroleum ether : Et2O) provided compound 2.28 as a clear yellowish liquid (0.0609 g, 0.163 mmol, 87%). IR nmax = 2953, 2875, 2841, 2250, 1641, 1595, 1565

-1 1 cm ; H NMR (CDCl3) d = 7.07 (s, 1H), 6.48 (d, J=2.4, 1H), 6.43 (d, J=2.1, 1H), 3.82 (s,

6H), 3.02 (dd, J=15, 2.4, 1H), 2.88 (m, 1H), 2.29 (m, 1H), 2.04 (m, 1H), 0.95 (m, 12H),

0.81 (m, 9H); NOESY-2D NMR (300 MHz, CDCl3): an off diagonal cross peak correlating

13 the d 6.43 and d 7.07 resonances; C NMR (CDCl3) 208.5, 158.6, 157.7, 147.5, 142.4,

137.9, 121.0, 107.1, 99.8, 60.8, 55.9, 55.4, 28.5, 21.6, 21.1, 19.1, 7.5, 3.5; HRMS m/e for

+ C22H34O3Si [M ] calculated 375.2355, found 375.2373.

163 Synthesis of 6-isopropyl-2,4-dimethoxy-5H-benzo[7]annulen-7(6H)-one (2.29)

O O

Compound 2.28 (0.0466 g, 0.124 mmol) was dissolved in degassed 1,2- dichloroethane (2 mL) and stirred. To this solution, trifluoroacetic acid (0.5 mL, 6.81 mmol) was added, and the reaction was allowed to stir for 24 h at room temperature, then

o using warm bath (40 C) under N2. After 4 h, the mixture was allowed to cool, afterward it dissolved in Et2O (30 mL) and extracted with H2O (3 C 30 mL). The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Preparative

TLC (5:1 petroleum ether : Et2O) provided compound 2.29 as a yellow liquid (0.0127 g,

0.049 mmol, 40 %) eluted first and recovered starting material (0.0121 g, 0.032 mmol, 26

-1 1 %). IR nmax = 2957, 2929, 2871, 1655, 1577, 1488 cm ; H NMR (CDCl3) d = 6.95 (d,

J=12.9, 1H), 6.54 (d, J=2.4, 1H), 6.47 (d, J=2.4, 1H), 6.11 (d, J=12.3, 1H), 3.83 (d, J=6.6,

6H), 3.16 (m, 1H), 2.93 (d, J=15.9, 1H), 2.25 (t, J=8.4, 1H), 1.91 (m, 1H), 0.85 (dd, J=16,

13 6.9, 6H); C NMR (CDCl3) 203.8, 158.7, 157.9, 141.9, 136.5, 129.4, 121.3, 108.1, 100.6,

+ + 56.9, 56.1, 55.5, 26.8, 21.2, 21.0, 19.5; HRMS m/e for C16H20O3 [M +H ] calculated

261.1491, found 261.1494.

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177 APPENDIX

STARTING MATERIAL (A)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 0.84029000 -0.56046800 -0.44656400 C 1.21570700 -1.27543200 0.67608600 C 0.64369700 -2.07168400 1.76206700 C -0.51060500 -2.86557100 1.53369900 C -0.16900700 0.23247800 -1.05688500 O -0.06499000 0.48019500 -2.36282500 C -1.34416300 0.84069000 -0.42801500 C -1.66441100 0.49404800 0.84777800 C -2.18155200 1.78913600 -1.26008600 H 0.74356000 0.01508200 -2.69712900 C 1.16410300 -1.99969200 3.07421900 H -0.92919700 -2.94123400 0.52506500 C -1.12489400 -3.54820000 2.58776200 CO 2.40500100 0.24269000 0.50635500 CO 2.29243600 -1.71339200 -0.98087300 H -1.07264500 -0.21372500 1.43135200 H -2.55544600 0.90544800 1.33071900 H -1.57654500 2.62447000 -1.64615000 H -2.61397700 1.27314600 -2.13181700 H -3.00266500 2.20018600 -0.65701600 C 1.70958000 1.28981900 1.79933300 C 3.87831500 -0.32213100 1.36933700 C 3.13054600 1.55401800 -0.55447400 C 1.30738400 -2.96324200 -1.81224500 C 3.51611100 -2.85917600 -0.25498900 C 3.21044500 -1.04589500 -2.41036600

178 O 1.26899300 1.95291700 2.63920700 O 4.82842300 -0.65163000 1.94357100 O 3.59223200 2.40327200 -1.18893700 O 0.67517900 -3.75225800 -2.37809000 O 3.82593900 -0.65399500 -3.31166100 O 4.27145400 -3.61452500 0.18685800 C 0.53947400 -2.67573100 4.12902800 C -0.60910200 -3.44755100 3.89223600 H 2.05329600 -1.39413300 3.27155000 H -2.01691100 -4.15239900 2.39114000 H 0.94508100 -2.59728600 5.14304700 H -1.10206000 -3.96754000 4.72054100

Energy = -3984.541676 (a.u.) Zero-point Energy = 52742.105000 (cm-1), 0.240311 (a.u.) Total = -3984.301366 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 52.5126 7.0074 -3984.2901986 101.3316 -3984.3383202

179

TRANSITION STATE (A)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.02599400 -0.62169400 -0.31590500 C 1.64361000 -1.32198400 0.71388600 C 1.13470300 -1.92438700 1.93074700 C -0.28958600 -2.27141600 1.98133800 C -0.33621100 -0.22438900 -0.59621200 O -0.70342800 0.01704200 -1.87948100 C -1.35573700 -0.25162400 0.36161700 C -1.04617100 -0.47878600 1.75446300 C -2.79473300 -0.17977200 -0.10617400 H 0.08773100 -0.07956800 -2.45458500 C 1.86725800 -1.92755900 3.12464200 H -0.74187300 -2.68883100 1.07952300 C -0.82117200 -2.78067000 3.22356000 CO 2.75430900 0.18000200 0.18514700 CO 2.29566500 -1.89566900 -1.05321800 H -0.21323500 0.07535700 2.19121100 H -1.91351300 -0.49161500 2.42248600 H -2.98602400 0.79224600 -0.59071000 H -3.02012000 -0.95323900 -0.85984200 H -3.49651600 -0.28388400 0.73330800 C 2.38357100 1.28889200 1.54640200 C 4.45536200 -0.25340600 0.63504900 C 3.01775900 1.43482200 -1.12116100 C 1.14507800 -3.17832300 -1.55979000 C 3.67546100 -2.97577700 -0.54573300 C 2.86701500 -1.33005000 -2.68240900

180 O 2.17928200 2.00186400 2.43786900 O 5.53677900 -0.53561000 0.93990600 O 3.14473900 2.25027600 -1.93236200 O 0.40555700 -4.00421000 -1.89800400 O 3.23562000 -0.98845800 -3.72647100 O 4.50766600 -3.69546800 -0.18890900 C -0.06875000 -2.76037200 4.38904900 C 1.28009600 -2.33624500 4.33366800 H 2.90963100 -1.59539400 3.11184700 H -1.84344600 -3.17377500 3.23155800 H -0.49491000 -3.10932000 5.33487500 H 1.88431000 -2.33894900 5.24723000

Energy = -3984.515271 (a.u.) Zero-point Energy = 52867.830000 (cm-1), 0.240884 (a.u.) Total = -3984.274388 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 54.9205 7.3330 -3984.2627018 102.9249 -3984.3115801

181

PROTONATED PRODUCT (A¢)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.35259200 -0.33745700 -0.37446100 C 1.69904800 -1.17352300 0.66982900 C 0.94552300 -2.04932300 1.49371800 C -0.50153300 -2.24867600 1.10880400 C 0.11289600 0.25484600 -0.81933900 O 0.13966800 1.08959900 -1.91882400 C -1.07879600 0.04308400 -0.17471300 C -1.28180500 -0.87042100 1.02889200 C -2.31908700 0.79663200 -0.59202400 H 1.07414300 1.25200000 -2.15803300 C 1.45400300 -2.66591800 2.65440000 C -1.25034800 -3.22105700 1.96282600 CO 2.99398900 0.25819600 0.58640300 CO 2.71543300 -1.59031800 -1.01452400 H -1.09810700 -0.31392900 1.96628600 H -2.35267800 -1.12832600 1.05128700 H -2.09220600 1.58153900 -1.32435300 H -3.06141300 0.10992400 -1.03752400 H -2.80659300 1.26349000 0.28266300 C 2.18930100 1.36166000 1.75209700 C 4.43864800 -0.28254900 1.56571200 C 3.77774500 1.52375500 -0.46024900 C 1.63411900 -2.67428200 -1.96041000 C 4.04576100 -2.74564200 -0.51539400 C 3.51499900 -0.75665400 -2.39341000 O 1.63497700 2.05441700 2.49651600

182 O 5.33691000 -0.59825300 2.22533500 O 4.28492700 2.33097000 -1.11804300 O 0.92662900 -3.35155900 -2.57999300 O 4.04380700 -0.24830900 -3.29034400 O 4.86969700 -3.49446000 -0.20010000 C -0.69538900 -3.82566300 3.05596000 C 0.65870400 -3.51852800 3.41685600 H -0.54136900 -2.66066000 0.07897900 H 2.48719800 -2.47113400 2.95521500 H -2.27842500 -3.45032000 1.66103000 H -1.26590200 -4.54255000 3.65524000 H 1.08350800 -3.97685500 4.31754900

Energy = -3984.518953 (a.u.) Zero-point Energy = 52788.485000 (cm-1), 0.240522 (a.u.) Total = -3984.278431 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 51.9102 6.9861 -3984.2672982 101.2832 -3984.3153969

183 STARTING MATERIAL (B)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 0.68280100 -0.82950100 -1.46413600 C 1.06834000 -1.54396800 -0.34442400 C 0.51119700 -2.35526600 0.73896400 C -0.65573100 -3.13096700 0.51240200 C -0.32546900 -0.04311700 -2.08556400 O -0.21891100 0.19275900 -3.39396500 C -1.50164700 0.57192600 -1.46647900 C -1.83156000 0.23429600 -0.19057000 C -2.32969700 1.51891800 -2.30963200 H 0.59029800 -0.27404000 -3.72475000 C 1.06079600 -2.30589400 2.03991600 H -1.08794400 -3.19043500 -0.49086000 C -1.25497600 -3.82188300 1.57071400 CO 2.24952200 -0.01823900 -0.52461600 CO 2.13711200 -1.97663000 -2.00646600 H -1.24763400 -0.47109000 0.40475000 H -2.72509300 0.65580100 0.27862800 H -1.71700200 2.34858900 -2.69530800 H -2.76015700 1.00002800 -3.18059700 H -3.15067200 1.93790200 -1.71269200 C 1.55574700 1.03445400 0.76609900 C 3.72790900 -0.58126200 0.32793100 C 2.96751000 1.28829900 -1.59858500 C 1.15165800 -3.22429100 -2.83775600 C 3.35489500 -3.12682900 -1.28380400 C 3.05417800 -1.31616400 -3.43792300 O 1.11563200 1.70720300 1.59827800 O 4.68246800 -0.91858000 0.89097500 O 3.42663000 2.12950400 -2.24557400

184 O 0.52192400 -4.01690400 -3.40126200 O 3.66899400 -0.93402900 -4.34373800 O 4.09896200 -3.89231100 -0.83967000 C 0.44581300 -2.99251300 3.10265200 C -0.71464200 -3.75243500 2.86434500 H 1.93934400 -1.68903900 2.24625500 H -2.16449900 -4.40363500 1.39148900 O 0.88766200 -2.85298600 4.39967500 H -1.18503500 -4.26230000 3.71003600 C 2.10147400 -3.56642000 4.74092300 H 1.95052200 -4.65493500 4.64124600 H 2.95035200 -3.24370200 4.11372500 H 2.30786900 -3.31915100 5.79039400

Energy = -4099.073146 (a.u.) Zero-point Energy = 59457.275000 (cm-1), 0.270907 (a.u.) Total = -4098.802239 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 54.7439 7.2107 -4098.7907478 102.9992 -4098.8396614

185

TRANSITION STATE (B)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.03238400 -0.69018300 -1.13588900 C 1.24869000 -1.43499100 0.01466700 C 0.36287300 -2.01862700 1.01503000 C -0.99275000 -2.34567400 0.60999800 C -0.11563300 -0.16492900 -1.83867000 O 0.11364700 0.11628600 -3.14340100 C -1.40344900 -0.12697500 -1.27416800 C -1.58064500 -0.33979400 0.12544300 C -2.61535500 0.03235500 -2.17988900 H -0.70000800 0.47422100 -3.56178800 C 0.70593600 -2.05895200 2.36874500 H -1.17172800 -2.65854000 -0.42004600 C -1.90687900 -2.82102200 1.60814400 CO 2.58263500 -0.02738200 -0.13269400 CO 2.34927400 -2.06328500 -1.49332900 H -0.86025700 0.07540800 0.83075900 H -2.60885100 -0.33469000 0.50106900 H -2.72656400 1.07752100 -2.52285400 H -2.56917300 -0.61978600 -3.07041900 H -3.54198400 -0.21435600 -1.64247000 C 1.87690100 1.16355900 1.00181200 C 4.00761200 -0.56444600 0.84377000 C 3.35900400 1.13750100 -1.31114200 C 1.28809600 -3.25760500 -2.30276900 C 3.49879900 -3.22685200 -0.68949400 C 3.29032100 -1.50868800 -2.95077300 O 1.43629500 1.93364500 1.75069100

186 O 4.92211000 -0.89876400 1.47420500 O 3.81405100 1.90248800 -2.05022300 O 0.59693100 -4.01967100 -2.83892200 O 3.87235700 -1.16570500 -3.89058200 O 4.19436900 -3.98982700 -0.16489700 C -0.23926000 -2.48229400 3.33813000 C -1.56122000 -2.85044800 2.94359900 H 1.70842400 -1.74443700 2.66583100 H -2.89784900 -3.16750700 1.29630900 O 0.00393700 -2.57359200 4.65696400 H -2.25882600 -3.18860300 3.71523200 C 1.33002300 -2.27328500 5.16663800 H 2.07867200 -2.95234100 4.72787500 H 1.59294800 -1.22102300 4.97157000 H 1.26185500 -2.44350300 6.24768600

Energy = -4099.062392 (a.u.) Zero-point Energy = 59813.350000 (cm-1), 0.272530 (a.u.) Total = -4098.789863 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 58.6094 7.7231 -4098.7775553 105.5089 -4098.8276607

187

PROTONATED PRODUCT (B¢)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.87666300 -0.37148900 -0.18658400 C 2.24626800 -1.23697900 0.82153200 C 1.50139700 -2.11074800 1.67488800 C 0.04244300 -2.29470700 1.31782100 C 0.63029600 0.21644100 -0.61801200 O 0.64524200 1.07766200 -1.69812700 C -0.55665700 -0.01603500 0.02586900 C -0.74468400 -0.93058500 1.22988300 C -1.80738600 0.71966700 -0.38969000 H 1.56927300 1.16232200 -2.00697300 C 2.05891700 -2.73552900 2.78577500 C 3.12098500 -4.14621200 5.07007000 C -0.69170400 -3.23710500 2.22162300 CO 3.51177400 0.23261100 0.77007700 CO 3.25103000 -1.60493300 -0.85633900 H -0.58341200 -0.36748200 2.16851400 H -1.81211100 -1.20579500 1.24111400 H -1.59368400 1.50709500 -1.12351300 H -2.54207700 0.02262600 -0.83329700 H -2.29541300 1.17954700 0.48837300 C 2.71861800 1.32441400 1.94972200 C 4.94837000 -0.33245200 1.73436900 C 4.27223100 1.51587700 -0.27027200 C 2.17740300 -2.72108600 -1.76168300

188 C 4.55912000 -2.76461900 -0.32728500 C 4.00692000 -0.77541400 -2.26881900 O 2.19349700 2.02335900 2.71126700 O 5.83900100 -0.69300200 2.38490300 O 4.76613400 2.34731100 -0.90847400 O 1.47606800 -3.43324000 -2.35025300 O 4.49891900 -0.26649900 -3.18721500 O 5.34426900 -3.53932400 0.02897100 C -0.11824600 -3.83962700 3.29253800 C 1.27833100 -3.59807400 3.59143300 H -0.00420900 -2.72783900 0.29704300 H 3.10844900 -2.54750400 3.02113600 H -1.74492800 -3.43500500 1.99057700 H -0.67364800 -4.51733500 3.94731000 O 1.72409200 -4.25602300 4.65491200 H 3.37994300 -3.09917500 5.28715500 H 3.77821600 -4.56596800 4.29369200 H 3.18470800 -4.74837500 5.98326600

Energy = -4099.077491 (a.u.) Zero-point Energy = 59982.960000 (cm-1), 0.273302 (a.u.) Total = -4098.804189 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 53.4862 7.0767 -4098.7929112 102.3360 -4098.8415099

189

STARTING MATERIAL (C)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.01231300 -0.63119600 -0.30770100 C 1.29899300 -1.37552200 0.81676000 C 0.71892400 -2.22803900 1.84477000 C -0.48377800 -2.83882600 1.73608800 C 0.09296100 0.20581200 -0.99307000 O 0.30519100 0.44286300 -2.28704200 C -1.09308600 0.87825700 -0.45910800 C -1.53105600 0.57072300 0.79137500 C -1.80487800 1.85516800 -1.36981700 H 1.10524100 -0.07190900 -2.56330600 H 1.33975700 -2.40610900 2.73177100 H -1.12224700 -2.72266900 0.85309300 H -0.84725200 -3.49836800 2.52997800 CO 2.56084700 0.10106000 0.72859300 CO 2.44257600 -1.84732600 -0.76736400 H -1.03174300 -0.16195700 1.42950900 H -2.43111400 1.04362800 1.19612100 H -1.12209900 2.64806600 -1.71507400 H -2.18536000 1.34343900 -2.26858000 H -2.65116100 2.31669600 -0.84372100 C 1.85528200 1.21329400 1.96623400 C 3.93381000 -0.55501500 1.68464500 C 3.43717400 1.33935400 -0.31053700 C 1.42598400 -3.04496200 -1.64019500

190 C 3.55794700 -3.06353200 0.01108800 C 3.47070900 -1.25271500 -2.15483400 O 1.42000500 1.93408800 2.75944600 O 4.81846600 -0.97561400 2.30103700 O 4.01376100 2.11547300 -0.94464500 O 0.76337900 -3.79861400 -2.21759200 O 4.15714900 -0.93221200 -3.03220600 O 4.22829500 -3.87376000 0.49051800

Energy = -3830.876695 (a.u.) Zero-point Energy = 42502.570000 (cm-1), 0.193656 (a.u.) Total = -3830.683039 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 45.4278 6.3900 -3830.6728556 97.3808 -3830.7191010

191 TRANSITION STATE (C)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.01562800 -0.63202300 -0.30710900 C 1.38866200 -1.36555200 0.83368600 C 0.62179300 -1.86926200 1.93353400 C -0.73793200 -2.18532900 1.82732200 C -0.26240100 -0.15716300 -0.78477000 O -0.45120500 -0.02084000 -2.11742900 C -1.41862300 -0.07391100 0.02076400 C -1.33525000 -0.19951600 1.43871300 C -2.76925200 -0.06322600 -0.67111300 H 0.39915400 -0.20713100 -2.57529800 H 1.05054200 -1.76420700 2.93861800 H -1.15827900 -2.57074900 0.89687900 H -1.26803200 -2.49190200 2.73644600 CO 2.68123100 0.02404600 0.52273500 CO 2.27433500 -2.00869600 -0.80706900 H -0.52480900 0.29062600 1.97621400 H -2.28057300 -0.20500700 1.99460600 H -2.86230700 0.83041500 -1.30904900 H -2.89432800 -0.93673000 -1.33333400 H -3.59005800 -0.04517000 0.05882100 C 2.09939300 1.27041700 1.68286900 C 4.15314400 -0.53683200 1.41943500 C 3.44112500 1.15986200 -0.70444400 C 1.12760100 -3.17427300 -1.56275100 C 3.42850200 -3.23059000 -0.08637600 C 3.21909600 -1.49649300 -2.27103700 O 1.74829600 2.06913500 2.44476300 O 5.07449000 -0.90515300 2.01388300 O 3.89744100 1.89059200 -1.47503100

192 O 0.39954400 -3.92628700 -2.05763100 O 3.81474200 -1.19848500 -3.21806300 O 4.11624100 -4.02550300 0.39288000

Energy = -3830.852130 (a.u.) Zero-point Energy = 42571.220000 (cm-1), 0.193969 (a.u.) Total = -3830.658161 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 47.9723 6.7256 -3830.6474432 99.0626 -3830.6944874

193 PROTONATED PRODUCT (C¢)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.34634600 -0.09832000 -0.06614200 C 1.57324800 -0.79249000 1.10110600 C 0.95623400 -1.95067100 1.55294900 C -0.53997900 -2.08952500 1.29313000 C 0.17128200 0.40488900 -0.70857500 O 0.27098900 1.16843200 -1.85238600 C -1.07453000 0.07446600 -0.21378200 C -1.29195500 -0.75407600 1.05072600 C -2.31483600 0.60824600 -0.87520700 H 1.19969600 1.45361800 -1.96215800 H 1.41353700 -2.56630500 2.33508100 H -0.74847700 -2.81281800 0.48818800 H -0.97793100 -2.54102300 2.19883300 CO 3.12688000 0.22685300 0.69484200 CO 2.33149300 -1.93089900 -0.34752400 H -1.11348700 -0.09715600 1.92418100 H -2.36451700 -1.00162000 1.08984900 H -2.08827600 1.28027800 -1.71199200 H -2.93507800 -0.22609400 -1.24960600 H -2.93374000 1.15355600 -0.13863800 C 2.67903100 1.63178300 1.72232300 C 4.46348000 -0.44535500 1.75627600 C 4.09183000 1.17327900 -0.54914900 C 1.17354200 -2.93082500 -1.32012400 C 3.44467300 -3.20459100 0.38396100 C 3.27771500 -1.42210300 -1.77425000 O 2.36346100 2.51110600 2.40064500 O 5.29141100 -0.85462400 2.44879600 O 4.69845800 1.81720600 -1.29191000

194 O 0.46832100 -3.60555000 -1.93910700 O 3.86331500 -1.15757300 -2.73824000 O 4.13935600 -4.02150300 0.81373000

Energy = -3830.883158 (a.u.) Zero-point Energy = 43056.895000 (cm-1), 0.196182 (a.u.) Total = -3830.686977 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 45.2915 6.4197 -3830.6767464 97.5967 -3830.7230944

195 STARTING MATERIAL (D)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 0.76608000 -0.58739600 -0.63584000 C 1.06831300 -1.32759900 0.48827400 C 0.46531900 -2.18917000 1.51362700 C -0.75642100 -2.73772600 1.29284700 C -0.15563400 0.24393300 -1.32638700 O 0.05125500 0.45079500 -2.62596600 C -1.32974200 0.94136400 -0.79775300 C -1.76900000 0.65780200 0.45766900 C -2.03289000 1.91707500 -1.71747800 H 0.85310500 -0.06912200 -2.89122900 C 1.26243400 -2.46109000 2.77324000 H -1.31921100 -2.55709300 0.37211200 H -1.21304500 -3.41153600 2.02584900 CO 2.32189800 0.17051000 0.35849700 CO 2.20149100 -1.78936000 -1.10950400 H -1.28382300 -0.07293900 1.10898200 H -2.66617300 1.14603600 0.84922900 H -1.33973600 2.69532200 -2.07303400 H -2.42627600 1.39892500 -2.60624100 H -2.86901000 2.40321700 -1.19712800 C 1.61148000 1.24497200 1.61770600 C 3.79068100 -0.36548300 1.25339500 C 3.10131300 1.44052200 -0.72000800 C 1.18742500 -3.00363700 -1.96067100 C 3.35939700 -2.98246200 -0.36225000 C 3.21390900 -1.17026300 -2.49293800 O 1.15608300 1.93438800 2.42789700

196 O 4.75522800 -0.65015400 1.82581500 O 3.59393200 2.24911900 -1.38406500 O 0.52928400 -3.77221200 -2.52311000 O 3.90854100 -0.81966100 -3.35243900 O 4.07106700 -3.78012200 0.07874500 H 2.30981400 -2.70438400 2.53882100 H 0.83605100 -3.30282800 3.33622300 H 1.27131800 -1.57783000 3.43393900

Energy = -3870.194349 (a.u.) Zero-point Energy = 48470.950000 (cm-1), 0.220850 (a.u.) Total = -3869.973499 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 47.5215 6.5764 -3869.9630191 98.4984 -3870.0097953

197 TRANSITION STATE (D)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 0.83780400 -0.67734200 -0.71223300 C 1.21197400 -1.47417700 0.37630700 C 0.45909900 -2.05797800 1.47226800 C -0.86909600 -2.42789400 1.25223900 C -0.42235200 -0.14484500 -1.17455100 O -0.57945100 0.11429400 -2.49073800 C -1.59538700 -0.11637500 -0.38658200 C -1.52553000 -0.33529500 1.01188000 C -2.93732000 -0.01924500 -1.08813000 H 0.27830500 -0.04529300 -2.94522100 C 1.03449100 -2.00709500 2.86088300 H -1.22475200 -2.69482000 0.25607900 H -1.45868900 -2.82686900 2.08493000 CO 2.53100700 -0.08679900 0.09568000 CO 2.06430200 -2.06170000 -1.29788400 H -0.70088100 0.07787200 1.59238500 H -2.46684400 -0.41132800 1.56701800 H -3.07114700 0.99479400 -1.50058300 H -3.01220000 -0.72070100 -1.93401100 H -3.76253300 -0.20912000 -0.38669600 C 1.98613300 1.16368600 1.26351900 C 4.00663300 -0.68117600 0.96459400 C 3.28110600 1.05693900 -1.12756200 C 0.88497900 -3.16471700 -2.09224800 C 3.19422400 -3.32481300 -0.62281200 C 3.00484200 -1.52951900 -2.75790700 O 1.65099700 1.97984700 2.01505300 O 4.94143500 -1.05811700 1.53387000

198 O 3.72634000 1.80114100 -1.89236000 O 0.14141800 -3.87671800 -2.62300800 O 3.60538100 -1.22108300 -3.69886300 O 3.87482000 -4.14256400 -0.17026600 H 2.05514600 -2.42290600 2.85762500 H 0.42382600 -2.56784200 3.58221200 H 1.12908800 -0.96490400 3.21719100

Energy = -3870.175711 (a.u.) Zero-point Energy = 48494.640000 (cm-1), 0.220958 (a.u.) Total = -3869.954753 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 49.9353 6.8839 -3869.9437828 100.0185 -3869.9912809

199 PROTONATED PRODUCT (D¢)

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.18294100 0.06935300 -0.39855100 C 1.42472800 -0.62906800 0.76846700 C 0.74788300 -1.67038500 1.38954400 C -0.72627000 -1.82379100 1.03622000 C 0.00205800 0.58860600 -1.02523000 O 0.11163700 1.34809100 -2.17103900 C -1.24569100 0.29329000 -0.51945600 C -1.47608300 -0.49774400 0.76483900 C -2.48332200 0.83544400 -1.17856500 H 1.04862900 1.60716900 -2.28265200 C 1.28471500 -2.51500400 2.49840100 H -0.84674700 -2.53180400 0.19812600 H -1.21751700 -2.31232900 1.89529600 CO 2.95229200 0.46150700 0.36948800 CO 2.23420800 -1.62532000 -0.79183300 H -1.30744700 0.18211500 1.62416500 H -2.54983000 -0.74304600 0.80387100 H -2.25516400 1.51580100 -2.00819400 H -3.10271200 0.00480300 -1.56444900 H -3.10599700 1.36824600 -0.43680900 C 2.47361100 1.86530100 1.39031100 C 4.29659200 -0.19747900 1.42260000 C 3.90577400 1.42429600 -0.86423700 C 1.03410000 -2.62283800 -1.70382800 C 3.36477600 -2.94278200 -0.17011800 C 3.12765800 -1.08863500 -2.24080000 O 2.15658500 2.75580500 2.05459700 O 5.11923500 -0.60322200 2.12567000 O 4.51772000 2.06436500 -1.60774400

200 O 0.29439900 -3.29244800 -2.28920700 O 3.70903800 -0.82692800 -3.20861600 O 4.05989400 -3.79920800 0.17644200 H 2.36542500 -2.39995000 2.64848000 H 1.04155700 -3.57532500 2.31383300 H 0.76425400 -2.25132400 3.43880100

Energy = -3870.205987 (a.u.) Zero-point Energy = 48928.300000 (cm-1), 0.222934 (a.u.) Total = -3869.983053 (a.u.)

Heat Enthalpy Free Temperature Capacity Correction Enthalpy Entropy Energy (Kelvin) (cal/mol/K) (kcal/mol) (a.u.) (cal/mol/K) (a.u.)

298 46.0869 6.4541 -3869.9727677 97.9724 -3870.0192941

201 E-2.6h

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 2.30171208 1.68023465 0.47444414 C 0.97468349 1.73112255 0.00353256 C 0.42406429 2.97684392 -0.37008211 C 1.19181485 4.14958367 -0.28959755 C 2.51957148 4.08620444 0.17517548 C 3.06990088 2.85139671 0.57521928 C 3.34917898 5.29130294 0.24549995 C 4.61897514 5.67951405 0.56344432 C 5.91492305 5.31401350 1.21474652 O 6.29738989 6.03775855 2.15222858 C 6.74652009 4.10283579 0.89835544 C 6.71273367 3.30531355 -0.20520986 C 7.78109774 3.83279588 1.98175540 H 7.44093434 2.48175465 -0.19708327 O 2.94285076 0.52370106 0.85434332 C 2.26269491 -0.72438576 0.65866484 O -0.86169454 3.13059604 -0.83204363 C -1.68881880 1.96033273 -0.91663171 H 0.37906956 0.82251932 -0.07487858 H 4.09338418 2.77775411 0.94918283 C 5.89402194 3.35731907 -1.45710583 H 8.51522833 4.65359306 2.02591975 H 7.31333031 3.78268750 2.97813137 H 8.31561266 2.89035676 1.78920197 CO 3.29924350 6.96087234 1.29428741 CO 4.01178310 6.66915709 -1.04260799 C 3.17323119 6.24963203 2.92004753 H 2.97918527 -1.49668191 0.97242008

202 H 1.35235482 -0.79784267 1.28116127 H 1.99812813 -0.87899118 -0.40353438 H -1.27662300 1.22155506 -1.62785532 H -1.82515288 1.48553543 0.07211544 H -2.65957612 2.31738396 -1.28581390 C 1.60682090 7.61880491 1.20094009 C 4.38567774 8.36093900 1.71280267 C 3.04056114 8.14412809 -1.27720819 C 5.65665065 7.30991349 -1.40738429 C 3.50095517 5.79635282 -2.51044189 O 3.09195638 5.81044846 3.99354983 O 0.52452607 8.04619043 1.20625530 O 5.08936674 9.24790029 1.96770728 O 2.48542576 9.13863195 -1.53684820 O 6.72373677 7.67881547 -1.69122530 O 3.17323369 5.28074022 -3.50397149 H 5.26977327 4.25219237 -1.54411393 H 6.56477287 3.31183973 -2.33454617 H 5.23909478 2.46920456 -1.52236368 H 0.75411876 5.10103734 -0.60056937

Energy = -4252.56027

203 Z-2.6h

Final cartesian coordinates (angstroms)

Cartesian representation

ATOM X Y Z C 1.98639234 2.19184630 0.01299233 C 0.68543124 2.26372264 -0.53245998 C 0.21895814 3.48429555 -1.04896542 C 1.04352270 4.62938058 -1.03183328 C 2.33406964 4.55117271 -0.48908294 C 2.80937270 3.32592149 0.04565508 C 3.21325621 5.72304365 -0.45746864 C 4.48796093 6.07635290 -0.09541453 C 5.72623588 5.62573920 0.61322085 O 6.04857398 6.19725417 1.66848849 C 6.57464628 4.49578789 0.11306677 C 6.24091641 3.80909378 -1.01036688 C 7.77318038 4.21034203 0.99048443 C 6.95298078 2.64288955 -1.63366168 O 2.35672341 0.95618052 0.49166524 C 3.66485677 0.85644821 1.07803972 O -1.03129379 3.65802773 -1.59089286 C -1.88822215 2.50679161 -1.64367780 H 3.81037796 3.29066557 0.47404190 H 5.34391974 4.13357392 -1.54786578 H 8.41513215 5.10261045 1.05962472 H 7.45185065 3.98612158 2.01999432 H 8.37527000 3.37246160 0.61538472 CO 3.21719239 7.45168809 0.49353968 CO 3.99524116 6.96353639 -1.78857153 C 2.97356110 6.84803252 2.15145897 H 4.45646751 1.08984562 0.34364454 H 3.76923740 1.52894933 1.94794340

204 H 3.76460523 -0.18665917 1.40630422 H -1.44386435 1.70459418 -2.25987199 H -2.10288701 2.11689118 -0.63242079 H -2.82195990 2.85267649 -2.10815376 H 7.80913071 2.27727573 -1.04987011 H 7.31504975 2.91481211 -2.64152809 H 6.25106157 1.80305447 -1.78158648 C 1.59445433 8.22771856 0.25449923 C 4.34585653 8.82230485 0.86806354 C 2.70077708 7.96829230 -2.51725552 C 5.48308335 7.98554221 -1.96725085 C 4.19738498 5.82156397 -3.13933561 O 2.82083607 6.45992939 3.23658162 O 0.56106873 8.75622285 0.16665762 O 5.08734995 9.68285627 1.11226718 O 1.90932299 8.65782777 -3.02368604 O 6.45873851 8.60096174 -2.11433052 O 4.31634961 5.11572608 -4.05965653 H 0.66678860 5.56859311 -1.44376792 H 0.07791739 1.35572833 -0.52923402

Energy = -4252.57372

205

VITA AUCTORIS

NAME SOMAIAH KHALID ALMUBAYEDH

YEAR OF BIRTH/COUNTRY 1988/SAUDI ARABIA

EDUCATION KING FAISAL UNIVERSITY, DAMMAM, SAUDI ARABIA, 2009, B.Sc-HONOURS IN CHEMISTRY

LAURENTIAN UNIVERSITY, SUDBURY, ONTARIO, CANADA, 2014-MSc IN CHEMICAL SCIENCE

PUBLICATION Almubayedh, S.; Chahma, M. New J. Chem. 2015, 39, 7738-7741.

206 DISSERTATION-RELATED CONFERENCE PRESENTATIONS

1. Presenting poster in CSC conference (2015, Ottawa). Ngenzi, R.; Mahmood, A.;

Almubayedh, S.; Green, J. R. “Vinylogous g-Carbonyl Cations for Remote

Functionalization”.

2. Presenting poster in CSC conference (2016, Halifax). Almubayedh, S.; Skieneh, J.;

Pouget, V.; Adams, S.; St.Onge, B.; Green, J. R. “Effects of Alkyne-Co2(CO)6

Complexation of Conjugation Synthetic Consequences”.

3. Presenting poster in CSC conference (2017, Toronto). Almubayedh, S.; Green, J.

R. “Alkynedicobalt Mediated Vinylogous Nazarov Reactions”.

4. Presenting poster in QOMSBOC conference (2017, Montreal). Almubayedh, S.;

Green, J. R. “Alkynedicobalt Mediated Vinylogous Nazarov Reactions”.

5. Presenting talk in CSC conference (2018, Edmonton). Almubayedh, S.; Green, J.

R. “Alkynedicobalt Mediated Vinylogous Nazarov Reactions”.

207